MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Biopharmaceutics and Drug Disposition' source. Wed, 08 Feb 2012 14:04:02 +0100 http://www.medworm.com/index.php?rid=5667365&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1770 ConclusionThe incidence of the poor metabolizer phenotype of desloratadine in the Jordanian population studied is similar to certain ethnic groups (e.g. Asian, Caucasians and Hispanic); however, it is lower than other populations (e.g. American Indians and Black). Copyright © 2012 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5667365 Mon, 23 Jan 2012 05:00:00 +0100 5667365 http://www.medworm.com/index.php?rid=5620276&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1770 ConclusionThe incidence of poor metabolizer phenotype of desloratadine in the Jordanian population studied is similar to certain ethnic groups (e.g. Asian, Caucasians and Hispanic); however, it is lower than other populations (e.g. American Indians and Black). Copyright © 2012 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5620276 Mon, 23 Jan 2012 05:00:00 +0100 5620276 http://www.medworm.com/index.php?rid=5620275&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1771 ConclusionsThese simulations suggest that a drug‐drug‐disease interaction which may significantly increase rivaroxaban exposure and may increase bleeding risk is possible. These simulations played a role in the decision to add cautionary language to the approved product labeling for rivaroxaban. Copyright © 2012 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5620275 Mon, 23 Jan 2012 05:00:00 +0100 5620275 http://www.medworm.com/index.php?rid=5572294&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1767 ABSTRACTIn 2005, a survey compared a number of commercial PBPK software available at the time, mainly focusing on ‘ready to use’ modelling tools. Since then, these tools and software have been further developed and improved to allow modellers to perform WB‐PBPK modelling including ADME processes at a high level of sophistication. This review presents a comparison of the features, values and limitations of both the ‘ready to use’ software and of the traditional user customizable software which are frequently used for the building and use of PBPK models, as well as the challenges associated with the various modelling approaches regarding their current and future use. PBPK models continue to be used more and more frequently during the drug development process since they represent a ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5572294 Fri, 06 Jan 2012 05:00:00 +0100 5572294 http://www.medworm.com/index.php?rid=5628824&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1773 ABSTRACTAclidinium bromide is a novel, inhaled long‐acting muscarinic antagonist with low systemic activity developed for the treatment of COPD. It is an ester compound rapidly hydrolyzed in plasma into inactive alcohol and acid metabolites. In this Phase I, open‐label study, the rates and routes of elimination of radioactivity following intravenous administration of [14 C]–aclidinium bromide were determined. The metabolites of aclidinium were also characterized and identified in plasma and excreta. Twelve healthy males were randomized (1:1) to receive a single intravenous 400 µg dose of [phenyl‐U‐14 C]– or [glycolyl‐U‐14 C]–aclidinium bromide (via 5‐min infusion) to label alcohol or acid metabolites of aclidinium, respectively. Safety and tolerability were ass... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5628824 Thu, 01 Dec 2011 05:00:00 +0100 5628824 http://www.medworm.com/index.php?rid=5620274&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1772 ABSTRACTThe effect of dosing time on the bioavailability of carbamazepine immediate‐release (IR) tablets was investigated when administrated to beagle dogs who were fasting, with coadministration of food (Co‐food), and 0.5 h before food and 2 h after food. The study was conducted using a single dose of 200 mg (tablets/solution) with a 2‐week washout period in a crossover design. Food intake significantly increased the rate and extent of tablets absorption. The Cmax (µg·ml‐1, 8.13/3.65) and tmax (h, 1.83/0.92) were increased more than twofold and the AUC0‐24 (µg·h·ml‐1, 20.09/8.19) was 2.5 times that of the values obtained under fasting conditions. The bioavailability of the tablets under fasting conditions was 91.2 %, but increased to 223.5 %, 182.8 % and 148.4% in t... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5620274 Thu, 01 Dec 2011 05:00:00 +0100 5620274 http://www.medworm.com/index.php?rid=5572293&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1769 ABSTRACTProspective simulations of human pharmacokinetic (PK) parameters and plasma concentration time curves using in vitro in vivo extrapolation (IVIVE) and physiologically‐based pharmacokinetic (PBPK) models are becoming a vital part of the drug discovery and development process. Here we present a strategy to deliver prospective simulations in support of clinical candidate nomination that utilizes a three stage approach of input parameter evaluation, model selection and multiple scenario simulation to predict the key components influencing human PK; absorption, distribution and clearance. The Simcyp® simulator is used to illustrate the approach and four compounds are presented as case studies. In general, the prospective predictions captured the observed clinical data well. Predicted... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5572293 Thu, 01 Dec 2011 05:00:00 +0100 5572293 http://www.medworm.com/index.php?rid=5552463&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1768 ABSTRACTPositive allosteric modulators (“potentiators”) of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) have been shown to display a mechanism‐based exposure‐response continuum in preclinical species with procognitive electrophysiologic and behavioral effects (“efficacy”) at low exposures and motor coordination disruptions at progressively higher exposures. Due to the dose‐capping nature of such motor coordination deficits, an exposure threshold‐mediated adverse event (CAE), the adequacy of separation between the maximal total plasma compound concentration (Cmax) at a predicted clinically efficacious oral dose and this AE was explored in early drug research with three AMPAR potentiators considered potential candidates for clinical... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5552463 Thu, 01 Dec 2011 05:00:00 +0100 5552463 http://www.medworm.com/index.php?rid=5505069&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.1761 In conclusion, the results of the present study, although based on limited data, suggested that the prediction for human CLb by allometry was greatly improved by the incorporation of protein binding. Human CLb prediction using rat data alone was not satisfactory. Additionally, QSPKR provides an alternative approach to allometry for the prediction of human biliary clearance. Copyright © 2011 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5505069 Thu, 01 Dec 2011 05:00:00 +0100 5505069 http://www.medworm.com/index.php?rid=5408411&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.780 This study provides information on the potential of hesperetin glucuronide conjugates to act as specific ABC transporter substrates or inhibitors and indicates that regio‐specific glucuronidation could affect the disposition of hesperetin. Copyright © 2011 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5408411 Tue, 01 Nov 2011 04:00:00 +0100 5408411 http://www.medworm.com/index.php?rid=5400869&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.779 In this study, we performed uptake experiments using Xenopus laevis oocytes to assess stereoselectivity in the inhibitory characteristics of flurbiprofen, ibuprofen and naproxen against hOAT1 and hOAT3. Uptake of p‐aminohippurate by hOAT1 was inhibited by each enantiomer of the three NSAIDs, and the inhibitory effect was superior in each (S)‐enantiomer around 10 μM. The apparent 50% inhibitory concentrations were estimated to be 0.615 μM for (S)‐flurbiprofen, 2.84 μM for (S)‐ibuprofen and 1.93 μM for (S)‐naproxen, and these values were significantly lower than those of the respective (R)‐enantiomers [(R)‐flurbiprofen: 2.35 μM, (R)‐ibuprofen: 6.14 μM, (R)‐naproxen: 5.26 μM]. Furthermore, the (S)‐NSAIDs at 3 μM reduced methotrexate accumulation in ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5400869 Tue, 01 Nov 2011 04:00:00 +0100 5400869 http://www.medworm.com/index.php?rid=5360542&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.776 ABSTRACTAnacetrapib is currently being developed for the oral treatment of dyslipidemia. A clinical study was conducted in healthy subjects to assess the potential for an interaction with orally administered digoxin. Anacetrapib was generally well tolerated when co‐administered with digoxin in the healthy subjects in this study. The geometric mean ratios (GMR) for (digoxin + anacetrapib/digoxin alone) and 90% confidence intervals (CIs) for digoxin AUC0‐last and AUC0‐∞ were 1.05 (0.96, 1.15) and 1.07 (0.98, 1.17), respectively, both being contained in the accepted interval of bioequivalence (0.80, 1.25), the primary hypothesis of the study. The GMR (digoxin + anacetrapib /digoxin alone) and 90% CIs for digoxin Cmax were 1.23 (1.14, 1.32). Median Tmax and mean apparent termin... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5360542 Mon, 31 Oct 2011 05:26:55 +0100 5360542 http://www.medworm.com/index.php?rid=5347722&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.775 ABSTRACTThe use of traditional/complementary/alternate medicines (TCAMs) in HIV/AIDS patients who reside in Southern Africa is quite common. Those who use TCAMs in addition to antiretroviral (ARV) treatment may be at risk of experiencing clinically significant pharmacokinetic (PK) interactions, particularly between the TCAMs and the protease inhibitors (PIs) and non‐nucleoside reverse transcriptase inhibitors (NNRTIs). Mechanisms of PK interactions include alterations to the normal functioning of drug efflux transporters, such as P‐gp and/or CYP isoenzymes, such a CYP3A4 that mediate the absorption and elimination of drugs in the small intestine and liver. Specific mechanisms include inhibition and activation of these proteins and induction via the pregnane X receptor (PXR). Several cl... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5347722 Wed, 26 Oct 2011 13:00:38 +0100 5347722 http://www.medworm.com/index.php?rid=5347720&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.778 The objective of the present study, therefore, was to formulate multi lamellar (MLVs) liposomal preparations of timolol maleate using their advantage of being less toxic compared to non – liposome – based drugs to be applied topically and to evaluate the in vivo performance of the prepared liposomes to extend the time of reduced IOP of glaucomatous rabbit’s eye measured using a standard Shiotz tonometer. The encapsulation efficiency of MLVs was measured using spectrophotometric technique. Differential Scanning calorimetry (DSC) was used to monitor the effects of timolol maleate in the absence and presence of cholesterol on liposome thermal behavior. Positively charged MLVs of timolol in the presence of lower amount of cholesterol (DPPC(7):CHOL(2):Timolol(2):SA(1) molar ratio) were fo... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5347720 Wed, 26 Oct 2011 13:00:18 +0100 5347720 http://www.medworm.com/index.php?rid=5347721&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.777 In conclusion, population‐based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population‐based pharmacokinetics to detect the effects of covariates. Copyright © 2011 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5347721 Wed, 26 Oct 2011 04:00:00 +0100 5347721 http://www.medworm.com/index.php?rid=5285895&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.774 ABSTRACTThis short communication is aimed to investigate whether the widely used hypolipidemic drug fenofibrate affects CYP2C11 and CYP2C6 in rats, both counterparts of human CYP2C9, known to metabolise many drugs including S‐warfarin and largely used non‐steroidal antiinflammatory drugs such as ibuprofen, diclofenac and others. The effects of fenofibrate on the expression of rat liver CYP2C11 and CYP2C6 were studied in both healthy Wistar rats and hereditary hypertriglyceridemic rats. Both strains of rats were fed on diet containing fenofibrate (0.1% w/w) for 20 days. Fenofibrate highly significantly suppressed the expression of mRNA of CYP2C11 and less that of CYP2C6 in liver microsomes of both rat strains; this effect was associated with a corresponding decrease in protein levels.... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5285895 Sat, 01 Oct 2011 04:00:00 +0100 5285895 http://www.medworm.com/index.php?rid=5250868&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.770 This study aims to characterize the pharmacodynamic properties of denosumab, a RANK ligand inhibitor, and ibandronate, a bisphosphonate, using an integrated bone homeostasis model in postmenopausal women. Mean temporal profiles of denosumab, serum and urine N‐telopeptide (sNTX, uNTX), lumbar spine bone mineral density (BMD) following denosumab administration, and urine C‐telopeptide (uCTX) and lumbar spine BMD upon ibandronate administration were extracted from the literature. A mechanistic model was developed that integrates denosumab pharmacokinetics with binding to RANK ligand and ibandronate inhibition of osteoclast precursor differentiation to active osteoclasts (AOC). Biomarker concentrations were linked to the AOC pool. The BMD was characterized by a turnover model with stimulat... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5250868 Sun, 25 Sep 2011 18:31:26 +0100 5250868 http://www.medworm.com/index.php?rid=5238000&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.773 ConclusionsZaleplon, 15 mg, in a novel, modified‐release formulation (SKP‐1041) had a time to peak plasma concentrations at 4–5 h postdose compared to 1.5 h for immediate‐release zaleplon, 10 mg. The pharmacokinetic profile suggests this formulation may be useful for treating middle‐of‐the‐night awakening. Copyright © 2011 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5238000 Thu, 22 Sep 2011 07:53:37 +0100 5238000 http://www.medworm.com/index.php?rid=5238001&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.771 ABSTRACTRadix Scutellariae is the dried root of the medicinal plant Scutellariae baicalensis Georgi. It exhibits a variety of therapeutic effects and has a long history of application in traditional formulations as well as in modern herbal medications. It has been confirmed that flavonoids are the most abundant constituents and induce these therapeutic effects. Six flavones are proven to be the major bioactive flavones in Radix Scutellariae existing in the forms of aglycones (baicalein, wogonin, oroxylin A) and glycosides (baicalin, wogonoside, oroxylin A‐7‐glucuronide). All six flavones are pharmacologically active and show great potential in the treatment of inflammation, cancers and virus‐related diseases. The current review covers the preparation of the herb Radix Scutellariae, q... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5238001 Mon, 19 Sep 2011 04:00:00 +0100 5238001 http://www.medworm.com/index.php?rid=5209102&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.772 ABSTRACTThe aim of the study was to investigate the role of breast cancer resistance protein (BCRP, ABCG2) in the transport of biochanin A and its metabolites. Transport studies were carried out in MDCK/bcrp1 as well as in control cells, and samples were analysed for biochanin A aglycone and metabolites using LC/MS/MS. In bidirectional transport studies biochanin A sulfate was detected in both apical and basolateral chambers after the addition of biochanin A. Analysis by RT‐PCR revealed that the enzyme sulfotransferase 1A1 is expressed in Madin‐Darby canine kidney (MDCK)‐II cells. After its intracellular formation, biochanin A sulfate was preferentially transported to the basolateral side in MDCK/Mock cells, whereas apical transport of biochanin A sulfate was predominant in MDCK/Bcrp... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5209102 Thu, 01 Sep 2011 04:00:00 +0100 5209102 http://www.medworm.com/index.php?rid=5184220&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.769 ABSTRACTEthyl (6R)‐6‐[N‐(2‐chloro‐4‐fluorophenyl)sulfamoyl]cyclohex‐1‐ene‐1‐carboxylate (TAK‐242) was metabolized to cyclohexene and phenyl ring moieties in non‐clinical pharmacokinetic studies and it was suggested that the cyclohexene ring moiety of TAK‐242 is tightly bound to endogenous macromolecules. After incubation of TAK‐242 and glutathione (GSH) in phosphate buffer (pH 7.4) at 37 °C, TAK‐242 reacted with GSH to produce a glutathione conjugate of the cyclohexene ring moiety of TAK‐242, which had been observed as a metabolite (M‐SG) in non‐clinical pharmacokinetic studies. Formation of M‐SG was time dependent with a first order reaction and M‐I, a metabolite from the phenyl ring moiety of TAK‐242, was also produced in parallel. The formati... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5184220 Wed, 31 Aug 2011 23:00:00 +0100 5184220 http://www.medworm.com/index.php?rid=5098021&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.766 ABSTRACTPolymeric microparticles suitable for topical and transdermal delivery systems were studied using poly d,l lactide (PLA), poly d,l lactide co glycoside (PLGA), poly (N‐isopropylacrylamide) (PNIPAM) and ethyl cellulose (EC). Drug encapsulation efficacy, microparticle stability and skin permeation studies of levothyroxine loaded microparticles were carried out using excised human skin, and the skin permeation pattern was observed using confocal laser scanning microscopy.It was found that ethyl cellulose microparticles had the highest drug encapsulation and minimal drug leakage during the 14 week storage period. The PNIPAM microparticles had the lowest drug encapsulation efficiency and a fast degradation rate. The PLGA microparticles exhibited a temperature dependent drug leakage.... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5098021 Tue, 02 Aug 2011 23:00:00 +0100 5098021 http://www.medworm.com/index.php?rid=5088676&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.765 ABSTRACTThe insect repellent N,N‐diethyl‐m‐toluamide (DEET) and sunscreen oxybenzone (OBZ) have been shown to produce synergistic permeation enhancement when applied concurrently in vitro and in vivo. The disposition of both compounds following intravenous administration (2 mg/kg of DEET or OBZ) and topical skin application (100 mg/kg of DEET and 40 mg/kg of OBZ) was determined in male Sprague‐Dawley rats. Pharmacokinetic analysis was also conducted using compartmental and non‐compartmental methods. A two‐compartment model was deemed the best fit for intravenous administration. The DEET and oxybenzone permeated across the skin to accumulate in blood, liver and kidney following topical skin application. Combined use of DEET and oxybenzone accelerated the disappearance of b... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5088676 Mon, 01 Aug 2011 23:00:00 +0100 5088676 http://www.medworm.com/index.php?rid=5079683&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.762 ABSTRACTA novel method, named as the plasma protein‐interaction QSAR analysis (PPI‐QSAR) was used to construct the QSAR models for human plasma protein binding. The intra‐molecular descriptors of drugs and inter‐molecular interaction descriptors resulted from the docking simulation between drug molecules and human serum albumin were included as independent variables in this method. A structure‐based in silico model for a data set of 65 antibiotic drugs was constructed by the multiple linear regression method and validated by the residual analysis, the normal Probability‐Probability plot and Williams plot. The R2 and Q2 values of the entire data set were 0.87 and 0.77, respectively, for the training set were 0.86 and 0.72, respectively. The results indicated that the fitted mode... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5079683 Wed, 27 Jul 2011 23:00:00 +0100 5079683 http://www.medworm.com/index.php?rid=5079684&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.764 ABSTRACTSeveral noncoding microRNAs (miR or miRNA) have been shown to regulate the expression of drug‐metabolizing enzymes and transporters. Xenobiotic drug‐induced changes in enzyme and transporter expression may be associated with the alteration of miRNA expression. Therefore, this study investigated the impact of 19 xenobiotic drugs (e.g. dexamethasone, vinblastine, bilobalide and cocaine) on the expression of ten miRNAs (miR‐18a, ‐27a, ‐27b, ‐124a, ‐148a, ‐324‐3p, ‐328, ‐451, ‐519c and −1291) in MCF‐7, Caco‐2, SH‐SY5Y and BE(2)‐M17 cell systems. The data revealed that miRNAs were differentially expressed in human cell lines and the change in miRNA expression was dependent on the drug, as well as the type of cells investigated. Notably, treatment with b... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5079684 Tue, 26 Jul 2011 23:00:00 +0100 5079684 http://www.medworm.com/index.php?rid=5109647&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.768 ABSTRACTIn vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) enzymes responsible for the oxidative metabolism of loxapine to 8‐hydroxyloxapine, 7‐hydroxyloxapine, N‐desmethylloxapine (amoxapine) and loxapine N‐oxide. These studies included use of cDNA‐expressed enzymes, correlation analysis with 12 phenotyped human liver microsomal samples, and use of selective inhibitors of cytochrome P450s. The resultant data indicated that loxapine was mainly metabolized by human liver microsomes to (i) 8‐hydroxyloxapine by CYP1A2, (ii) 7‐hydroxyloxapine by CYP2D6, (iii) N‐desmethyloxapine by CYP3A4 and (iv) loxapine N‐oxide by CYP3A4. The involvement of flavin‐containing monooxygenase (FMO) in the formation of loxapine N‐oxide was also observed. Copyright ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5109647 Thu, 30 Jun 2011 23:00:00 +0100 5109647 http://www.medworm.com/index.php?rid=5098020&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.761 ConclusionChlorin‐e6 is a potential sonosensitizer for fluorescence imaging as well as for sonodynamic therapy for cancer. The anti‐tumor effect of ultrasound could be enhanced in the presence of Ce6, which might be involved in a sonochemical mechanism. Copyright © 2011 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5098020 Thu, 30 Jun 2011 23:00:00 +0100 5098020 http://www.medworm.com/index.php?rid=5088675&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.767 ABSTRACTThe distribution characteristics of clarithromycin (CAM) and azithromycin (AZM), macrolide antimicrobial agents, in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) were evaluated. In the in vivo animal experiments, the time‐courses of the concentrations of CAM and AZM in ELF and AMs following oral administration (50 mg/kg) to rats were markedly higher than those in plasma, and the area under the drug concentration–time curve (AUC) ratios of ELF/plasma of CAM and AZM were 12 and 2.2, and the AUC ratios of AMs/ELF were 37 and 291, respectively. In the in vitro transport experiments, the basolateral‐to‐apical transport of CAM and AZM through model lung epithelial cell (Calu‐3) monolayers were greater than the apical‐to‐basolateral transport. MDR1 subs... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5088675 Thu, 30 Jun 2011 23:00:00 +0100 5088675 http://www.medworm.com/index.php?rid=5079682&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.763 ABSTRACTN‐aromatic acyl‐amino acid conjugates possess a colon‐targeted property, implying that such conjugates are stable and are not absorbable until reaching the large intestine in which they are microbially converted (hydrolysed) to the parent drugs that are therapeutically active. To investigate the structural effect of N‐aromatic acyl‐amino acid conjugates on the large intestinal deconjugation, the hydrolysis of various N‐aromatic acyl‐amino acid conjugates was examined in the cecal contents. On incubation of conjugates with glycine, d or/and l forms of alanine or phenylalanine in the cecal contents, the conjugates with d amino acids were not hydrolysed. The other conjugates are susceptible to the hydrolysis, the rates of which decreased as the size of the substituent on... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=5079682 Thu, 30 Jun 2011 23:00:00 +0100 5079682 http://www.medworm.com/index.php?rid=4999374&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.760 ABSTRACTThe ‘relative activity factor’ (RAF) compares the activity per unit of microsomal protein in recombinantly expressed cytochrome P450 enzymes (rhCYP) and human liver without separating the potential sources of variation (i.e. abundance of enzyme per mg of protein or variation of activity per unit enzyme). The dimensionless ‘inter‐system extrapolation factor’ (ISEF) dissects differences in activity from those in CYP abundance. Detailed protocols for the determination of this scalar, which is used in population in vitro–in vivo extrapolation (IVIVE), are currently lacking. The present study determined an ISEF for CYP2C9 and, for the first time, systematically evaluated the effects of probe substrate, cytochrome b5 and methods for assessing the intrinsic clearance (CLint). ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4999374 Thu, 30 Jun 2011 23:00:00 +0100 4999374 http://www.medworm.com/index.php?rid=4913849&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.759 ABSTRACTThe antioxidant response element (ARE) is a critical regulatory element for the expression of many phase II drug metabolizing enzymes (DME), phase III transporters and antioxidant enzymes, mediated by the transcription factor Nrf2. The aim of this study was to examine the potential activation and synergism of Nrf2‐ARE‐mediated transcriptional activity between four common phytochemicals present in cruciferous vegetables; the indoles: indole‐3‐carbinol (I3C), 3,3′‐diindolylmethane (DIM); and the isothiocyanates (ITCs): phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). The cytotoxicity of the compounds was determined in a human liver hepatoma cell line (HepG2‐C8). The combination index was calculated to assess the synergistic effects on the induction of ARE‐medi... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4913849 Tue, 07 Jun 2011 23:00:00 +0100 4913849 http://www.medworm.com/index.php?rid=4937258&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.757 ABSTRACTThe two erythropoiesis stimulating agents (ESAs), short acting recombinant human erythropoietin (EPO) and long acting continuous erythropoietin receptor activator (CERA), have been hypothesized to share an in vivo elimination pathway that involves binding to erythropoietin receptor (EPOR) and subsequent internalization. A physiologically based recirculation model and a pharmacokinetic tracer interaction methodology (TIM) were used to compare the in vivo interaction kinetics with EPOR between the two ESAs in adult sheep. Animals treated with EPO experienced a greater EPOR up‐regulation than those treated with CERA, as evidenced by an eightfold‐higher initial EPOR normalized production rate constant, ksyn/R0, versus a twofold‐larger EPOR degradation rate constant, kdeg. In agre... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4937258 Sat, 30 Apr 2011 23:00:00 +0100 4937258 http://www.medworm.com/index.php?rid=4913848&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.756 ABSTRACTDanoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half‐life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal‐vein‐cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal‐vein‐cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4913848 Sat, 30 Apr 2011 23:00:00 +0100 4913848 http://www.medworm.com/index.php?rid=4885932&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.758 (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4885932 Sat, 30 Apr 2011 23:00:00 +0100 4885932 http://www.medworm.com/index.php?rid=4822203&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.755 ABSTRACTThe aim of the present study was to investigate the mechanisms for membrane transport of metformin in human intestinal epithelial Caco‐2 cells. The mRNA of not only organic cation transporter (OCT) 3, but also OCT1 and OCT2, was expressed in Caco‐2 cells. The uptake of 100 µm metformin at the apical membrane of Caco‐2 cells grown on porous filter membrane was significantly greater than that at the basolateral membrane. The apical uptake of 100 µm metformin in Caco‐2 cells grown on plastic dishes was inhibited significantly by 1 mm unlabeled metformin, quinidine and pyrilamine, indicating that a specific transport system is involved in the apical uptake of metformin in Caco‐2 cells. The apical uptake of 100 µm metformin in Caco‐2 cells was decreased by acidifi... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4822203 Sat, 30 Apr 2011 23:00:00 +0100 4822203 http://www.medworm.com/index.php?rid=4736265&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.754 This study aimed to investigate the effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats. Intravenous (6 mg/kg) or oral (2 mg/kg) etoposide was administered to rats in the absence and the presence of oral curcumin (0.4, 2 or 8 mg/kg). The effects of curcumin on the P‐glycoprotein (P‐gp) and CYP3A4 activity was also evaluated. Curcumin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration (IC50) of 2.7 µM. In addition, curcumin (10 µm) significantly enhanced the cellular accumulation of rhodamine‐123 in MCF‐7/ADR cells overexpressing P‐gp. Compared with the control group (given etoposide alone), curcumin (2 or 8 mg/kg) increased significantly the oral bioavailability (AUC and Cmax) of etoposide. Consequently, the e... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4736265 Fri, 22 Apr 2011 16:27:14 +0100 4736265 http://www.medworm.com/index.php?rid=4686596&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.750 AbstractIn conscious and co‐operating patients, oral drug delivery remains the preferable route of drug administration. However, not all drugs possess the desirable physicochemical and pharmacokinetic properties which favor oral administration mainly due to poor bioavailability. This has in some cases led to the choice of other routes of administration, which may compromise the convenience and increase the risk of non‐compliance. Poor bioavailability has necessitated the administration of higher than normally required oral doses which often leads to economic wastages, risk of toxicity, erratic and unpredictable responses. The challenge over the years has been to design techniques that will allow oral administration of most drugs, irrespective of their properties, to achieve a therapeut... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4686596 Thu, 31 Mar 2011 23:00:00 +0100 4686596 http://www.medworm.com/index.php?rid=4654447&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.752 AbstractMicafungin, a new echinocandin antifungal agent, has been used widely for the treatment of various fungal infections in human populations. Micafungin is predominantly cleared by biliary excretion and it binds extensively to plasma proteins. Micafungin body weight‐adjusted clearance is higher in neonates than in adults, but the mechanisms underlying this difference are not understood. Previous work had revealed the roles of sinusoidal uptake (Na+‐taurocholate co‐transporting peptide, NTCP; organic anion transporting polypeptide, OATP) as well as canalicular efflux (bile salt export pump, BSEP; breast cancer resistance protein, BCRP) transporters in micafungin hepatobiliary elimination. In the present study, the relative protein expression of hepatic transporters was compared b... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4654447 Tue, 01 Mar 2011 00:00:00 +0100 4654447 http://www.medworm.com/index.php?rid=4644766&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.753 AbstractVenlafaxine and its metabolite desvenlafaxine are serotonin‐norepinephrine reuptake inhibitors currently prescribed for the treatment of depression. Previously, it was reported that venlafaxine is an inducer of MDR1, the gene responsible for P‐glycoprotein (P‐gp). The present study expanded upon these findings by examining the effect of venlafaxine and desvenlafaxine on the expression of both P‐gp and the breast cancer resistance protein (BCRP) in human brain endothelial cells (HBMEC), an in vitro model of the blood–brain barrier (BBB). The HBMEC were treated for 1 h with various concentrations (500 nM to 50 µM) of venlafaxine and desvenlafaxine. Western blot analysis revealed treatment with venlafaxine significantly induced the expression of P‐gp (2‐fold) and BC... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4644766 Tue, 01 Mar 2011 00:00:00 +0100 4644766 http://www.medworm.com/index.php?rid=4606867&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.751 This study therefore aimed to assess the viability and integrity of tissue from patients undergoing pancreatoduodenectomy, for use in cross‐species Ussing chamber studies. Electrical parameters (potential difference, mV; short‐circuit current, µA.cm−2; resistance, Ω.cm2) were monitored over the duration of each experiment, as was the permeability of the paracellular marker atenolol. The permeability values (Papp; cm/s × 10−6) for a training‐set of compounds, displaying a broad range of physicochemical properties and known human fraction absorbed values, were determined in both rat and human jejunum, as well as Caco‐2 cell monolayers. The results indicate that human jejunum sourced from pancreatoduodenectomy remained viable and intact for the duration of experiments. Permeabi... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4606867 Tue, 01 Mar 2011 00:00:00 +0100 4606867 http://www.medworm.com/index.php?rid=4536810&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.748 Conclusion. Ciprofloxacin decreases the metabolism of itraconazole, most likely through inhibition of CYP3A4. The dosage of itraconazole should be reduced and its therapeutic outcome should be monitored closely when these two agents are concomitantly administered. Copyright © 2011 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4536810 Tue, 01 Mar 2011 00:00:00 +0100 4536810 http://www.medworm.com/index.php?rid=4536809&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.747 AbstractSugammadex is a modified γ‐cyclodextrin which rapidly reverses rocuronium‐and vecuronium‐induced neuromuscular blockade. Previous studies suggest that sugammadex is mostly excreted unchanged via the kidneys. This single‐center, open‐label, non‐randomized study used 14C‐labeled sugammadex to further investigate the excretion, metabolic and pharmacokinetic (PK) profiles of sugammadex in six healthy male volunteers. 14C‐labeled sugammadex 4 mg/kg (0.025 MBq/kg of 14C‐radioactivity) was administered as a single intravenous bolus. Blood, urine, feces and exhaled air samples were collected at pre‐defined intervals for assessment of sugammadex by liquid chromatography‐mass spectrometry (LC‐MS) and for radioactivity measurements. Adverse events were also assess... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4536809 Tue, 01 Mar 2011 00:00:00 +0100 4536809 http://www.medworm.com/index.php?rid=4518414&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.749 AbstractKetoconazole and rifampin are the most widely used compounds examined in recent drug–drug interaction (DDI) studies, and they have multiple roles in modulating drug metabolizing enzymes and transporters. To determine the underlying mechanisms of DDI, this study was performed to investigate the inhibitory effects of ketoconazole and rifampin on the functions of OAT1 and OATP1B1, and to evaluate the potential of ketoconazole and rifampin for DDI with substrate drugs for these transporters in a clinical setting. Ketoconazole inhibited OATP1B1‐mediated transport activity, while rifampin inhibited OAT1 and OATP1B1. Inhibition by rifampin and ketoconazole of the uptake of olmesartan, a substrate for OAT1 and OATP1B1, was evaluated in oocytes overexpressing these transporters. The Ki ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4518414 Fri, 25 Feb 2011 16:39:50 +0100 4518414 http://www.medworm.com/index.php?rid=4344307&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.741 AbstractON 01210.Na (Ex‐RAD®) is a novel small molecule under development by Onconova Therapeutics, Inc. as a radiation protection agent. The purpose of this investigation was to evaluate the effect of various formulation approaches on the systemic exposure of ON 01210.Na. In vitro experiments were used to characterize the plasma binding and metabolic stability of ON 01210.Na using hepatocytes from several animal species (mouse, rat, rabbit, dog, monkey and human). In vivo studies were performed in rats, rabbits, dogs and monkeys, and involved several routes of administration (intravenous, subcutaneous, oral). Plasma protein binding was high across species (>83%), and the rate of ON 01210.Na metabolism was highest in rat and mouse hepatocytes. After intravenous administration, ON 012... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4344307 Fri, 14 Jan 2011 00:00:00 +0100 4344307 http://www.medworm.com/index.php?rid=4478525&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.746 AbstractLutein is a carotenoid found mainly in green leafy vegetables and is located in the macula lutea in the human eye. An intake of lutein as food is needed since humans cannot synthesize it de novo. Although lutein has received much attention recently due to its antioxidant activities, little information about the pharmacokinetic properties of lutein is available. Lutein emulsion formulation was used and the pharmacokinetics of lutein emulsion after oral administration to rats was investigated. The bioavailability of lutein using this formulation was calculated to be 5.20%. It was found that a large amount of lutein was accumulated in the intestinal mucosa. The absorption of orally administered compounds in the intestine can be enhanced by interaction with food or food components. Thu... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4478525 Sat, 01 Jan 2011 00:00:00 +0100 4478525 http://www.medworm.com/index.php?rid=4400985&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.745 The objective of the present study was to elucidate the mechanisms of intestinal transport of bis(12)‐hupyridone (B12H) to predict its oral bioavailability. The effect of the B12H concentration and the contribution of the drug efflux transporters, P‐glycoprotein (P‐gp or ABCB1) and multidrug resistance‐associated proteins (MRPs or ABCC) on B12H absorption were measured and evaluated using the human intestinal epithelial Caco‐2 cell monolayer in the presence of transporter inhibitors. The results indicated that B12H was absorbed in a dose‐dependent manner at concentrations ranging from 132 to 264 µM. However, only apical efflux was observed in the directional transport studies for B12H below 88 µM (Papp(AP‐to‐BL): virtually zero; Papp(BL‐to‐AP): 1.591 ± 0.071 × 1... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4400985 Sat, 01 Jan 2011 00:00:00 +0100 4400985 http://www.medworm.com/index.php?rid=4344306&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.742 This study confirms that the rat intestinal PepT1, Mrp2 and Mrp4, but not P‐gp are functionally induced by 1,25(OH)2D3 treatment via the vitamin D receptor (VDR). Copyright © 2011 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4344306 Sat, 01 Jan 2011 00:00:00 +0100 4344306 http://www.medworm.com/index.php?rid=4327409&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.743 AbstractA feedback receptor regulation model was incorporated into a pharmacodynamic model to describe the stimulation of hemoglobin (Hb) production by endogenous erythropoietin (EPO). The model considers the dynamic changes that take place in the EPO receptor (EPOR) pool under phlebotomy‐induced anemia. Using a 125I‐rhEPO tracer the EPO clearance changes are evaluated longitudinally prior to and following phlebotomy‐induced anemia indirectly to evaluate changes in the EPOR pool size, which has been shown to be linearly related to the clearance. The proposed model simultaneously captures the general behavior of temporal changes in Hb relative to EPO plasma clearance in five lambs (r = 0.95), while accounting for the confounding variables of phlebotomy and changes in the blood volume ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4327409 Sat, 01 Jan 2011 00:00:00 +0100 4327409 http://www.medworm.com/index.php?rid=4295990&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.744 In conclusion, the pharmacokinetics of 5‐FU is not affected by hepatic fibrosis, unlike that of many hepatically metabolized drugs. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4295990 Thu, 30 Dec 2010 00:10:19 +0100 4295990 http://www.medworm.com/index.php?rid=4295991&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.739 AbstractThe aim of this work was to evaluate the performance of various compliance parameters in order to identify those which best assess the impact of compliance on therapeutic issues. We will discuss the particularities and restrictions of these parameters by considering two criteria, namely sensitivity index and reliability, which respectively describe strength and robustness of the relationship between these parameters and compliance. Using real and virtual data, performance analysis of compliance parameters was carried out for drugs whose pharmacokinetic properties govern the time course of their actions. Within this context, it was found that the percentage of taken doses (PTD), the most widely used parameter, poorly performed in the evaluation of the therapeutic impact of complianc... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4295991 Tue, 28 Dec 2010 00:00:00 +0100 4295991 http://www.medworm.com/index.php?rid=4282283&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.740 AbstractHemorrhagic shock involves loss of a substantial portion of circulating blood volume leading to diminished cardiac output and oxygen delivery to peripheral tissues. In situations where an immediate resuscitation cannot be provided, pharmacotherapy with a novel combination of Δ9‐tetrahydro‐cannabinol (THC) and celecoxib (CEL) is currently investigated as an alternative strategy to prevent organ damage. In the present study, 28 Yorkshire × Landrace pigs were used to study the pharmacokinetics of THC and CEL in an established porcine model of hemorrhagic shock. Pigs in hemorrhagic shock received 0.5, 1 or 4 mg/kg THC and 2 mg/kg CEL, while normotensive pigs received 1 mg/kg THC and 2 mg/kg CEL by intravenous injection. THC and CEL plasma concentrations were simultaneousl... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4282283 Thu, 23 Dec 2010 16:17:52 +0100 4282283 http://www.medworm.com/index.php?rid=4267625&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.734 AbstractThe pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague‐Dawley rats after intravenous (i.v.) and oral (p.o.) administrations. Following a single i.v. bolus dose, the mean plasma clearance (CL) of DBM was low compared with the hepatic blood flow. DBM displayed a high volume of distribution (Vss). The elimination terminal t1/2 was long. The mean CL, Vss and AUC0−∞/dose were similar between the i.v. 10 and 10 mg/kg doses. After single oral doses (10, 50 and 250 mg/kg), the absolute oral bioavailability (F*) of DBM was 7.4%–13.6%. The increase in AUC was not proportional to the oral doses, suggesting non‐linearity. In silico prediction of oral absorption also demonstrated low DBM absorption in vivo. A... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4267625 Sun, 19 Dec 2010 17:13:13 +0100 4267625 http://www.medworm.com/index.php?rid=4238754&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.733 AbstractChemotherapy‐induced anemia is a frequent complication in cancer treatment. The aim was to develop a pharmacokinetic (PK) model that describes the time‐dependent decline of epoetin alfa (rHuEPO) clearance following thrice (t.i.w.) or once (q.w.) weekly subcutaneous injections in cancer patients using a population PK approach. Serum concentrations of rHuEPO were available retrospectively from a phase I study. A one‐compartment model with first‐order elimination described rHuEPO PK. Sequential zero‐ and first‐order (ka) processes with duration (tlag) characterized the absorption. Population PK analysis was performed using NONMEM. The influence of several covariates was tested. Model evaluation was performed using visual predictive check. Precision of parameter estimates w... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4238754 Tue, 07 Dec 2010 00:00:00 +0100 4238754 http://www.medworm.com/index.php?rid=4238753&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.735 AbstractThe permeation and efflux of six polysubstituted flavonoids isolated from Crossostephium chinense, a Chinese traditional and herbal drug for the treatment of diabetes, were investigated using the Caco‐2 cell monolayer. The six flavonoids (selagin, apometzgerin, tricetin‐3′,4′,5′‐trimethylether, quercetagetin‐3,6,7‐trimethylether, hispidulin and quercetagetin) sharing a similar parent skeleton structure with varied substituents in the heterocyclic ring B were selected for the study. Quercetagetin exhibited a low bi‐directional permeability comparable to that of atenolol, suggesting a paracellular diffusion mechanism. The remaining compounds exhibited time‐ and concentration‐ dependent permeation with apparent permeability coefficient (Papp) values in the range ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4238753 Mon, 01 Nov 2010 00:00:00 +0100 4238753 http://www.medworm.com/index.php?rid=4230927&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.738 The objective was to determine the impact of those plasma factors on PDK4 mRNA and to develop and validate a population mathematical model to differentiate aging, diet and disease effects on muscle PDK4 expression. The Goto‐Kakizaki (GK) rat, a polygenic non‐obese model of type 2 diabetes, was used as the diabetic animal model. Muscle PDK4 mRNA expression was examined by real‐time QRTPCR. Groups of GK rats along with controls fed with either a normal or high fat diet were killed at 4, 8, 12, 16 and 20 weeks of age. Plasma corticosterone, insulin and free fatty acids were measured. The proposed mechanism‐based model successfully described the age, disease and diet effects and the relative contribution of these plasma regulators on PDK4 mRNA expression. Muscle growth reduced the PDK4... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4230927 Mon, 01 Nov 2010 00:00:00 +0100 4230927 http://www.medworm.com/index.php?rid=4215287&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.736 AbstractMNP001 is a newly synthesized 3‐carbamyl‐4‐methylpyrrole analog with dual pharmacophores simultaneously to inhibit phosphodiesterase type 4 (PDE4) and to antagonize L‐type calcium channels. The physicochemical properties of MNP001, including solubility, pKa, Log P, plasma protein binding and plasma/blood partitioning, were determined to support the pharmacokinetic characterization. The preclinical pharmacokinetic parameters were determined in an in vivo rat model and the metabolic pathways of MNP001 were characterized by incubating the compound in vitro in rat or human microsomes/supersomes cocktails. MNP001 was found to have a low solubility in simulated intestinal fluid but a high solubility in simulated gastric fluid. MNP001 is a highly lipophilic compound with a Log P v... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4215287 Mon, 01 Nov 2010 00:00:00 +0100 4215287 http://www.medworm.com/index.php?rid=4208794&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.737 AbstractHypertension is the most common comorbidity and major risk factor in patients with erectile dysfunction. The pharmacokinetics of mirodenafil, used for the treatment of erectile dysfunction, after the intravenous and oral administration (20 mg/kg) to 6‐week‐old rats (with blood pressure within the normotensive range) and 16‐week‐old spontaneously hypertensive rats (SHRs) and their age‐matched control normotensive Kyoto–Wistar (KW) rats, and 16‐week‐old deoxycorticosterone acetate–salt‐induced hypertensive rats (DOCA–salt rats) and their age‐matched control Sprague–Dawley (SD) rats were compared. It was found that time‐averaged renal clearance (Clr) was of minor importance and that time‐averaged non‐renal clearance (Clnr) was dominant. In both 6‐ a... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4208794 Mon, 01 Nov 2010 00:00:00 +0100 4208794 http://www.medworm.com/index.php?rid=4192020&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.732 AbstractThe creation of virtual populations allows the estimation of pharmacokinetic parameters, such as metabolic clearance in extreme individuals rather than the ‘average human’. Prediction of variability in metabolic clearance within genetically diverse populations relies on understanding the covariation in the expression of enzymes. A number of statistically significant positive correlations have been observed in the hepatic expression of cytochrome P450 drug metabolising enzymes. However, these rarely provided a quantitative description of the relationships which is required in creating virtual populations. Collation of data from 40 human liver microsomal samples in the current study indicated a significant positive relationship between hepatic microsomal CYP3A5*1/*3 and CYP3A4 co... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4192020 Mon, 01 Nov 2010 00:00:00 +0100 4192020 http://www.medworm.com/index.php?rid=4110245&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.730 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4110245 Thu, 30 Sep 2010 23:00:00 +0100 4110245 http://www.medworm.com/index.php?rid=4089832&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.731 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4089832 Thu, 30 Sep 2010 23:00:00 +0100 4089832 http://www.medworm.com/index.php?rid=4041667&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.729 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4041667 Thu, 30 Sep 2010 23:00:00 +0100 4041667 http://www.medworm.com/index.php?rid=4005401&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.728 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4005401 Wed, 29 Sep 2010 13:44:14 +0100 4005401 http://www.medworm.com/index.php?rid=3738596&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.719 In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3738596 Fri, 09 Jul 2010 23:00:00 +0100 3738596 http://www.medworm.com/index.php?rid=3995334&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.725 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3995334 Wed, 30 Jun 2010 23:00:00 +0100 3995334 http://www.medworm.com/index.php?rid=3970422&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.722 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3970422 Wed, 30 Jun 2010 23:00:00 +0100 3970422 http://www.medworm.com/index.php?rid=3955799&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.720 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3955799 Wed, 30 Jun 2010 23:00:00 +0100 3955799 http://www.medworm.com/index.php?rid=3939517&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.721 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3939517 Wed, 30 Jun 2010 23:00:00 +0100 3939517 http://www.medworm.com/index.php?rid=3922223&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.723 (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3922223 Wed, 30 Jun 2010 23:00:00 +0100 3922223 http://www.medworm.com/index.php?rid=3916883&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.724 (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3916883 Wed, 30 Jun 2010 23:00:00 +0100 3916883 http://www.medworm.com/index.php?rid=3835954&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.713 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3835954 Wed, 30 Jun 2010 23:00:00 +0100 3835954 http://www.medworm.com/index.php?rid=3835953&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.712 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3835953 Wed, 30 Jun 2010 23:00:00 +0100 3835953 http://www.medworm.com/index.php?rid=3835952&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.711 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3835952 Wed, 30 Jun 2010 23:00:00 +0100 3835952 http://www.medworm.com/index.php?rid=3835951&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.709 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3835951 Wed, 30 Jun 2010 23:00:00 +0100 3835951 http://www.medworm.com/index.php?rid=3835950&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.719 (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3835950 Wed, 30 Jun 2010 23:00:00 +0100 3835950 http://www.medworm.com/index.php?rid=3660402&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.718 Asenapine is a psychopharmacologic agent approved in the United States for the acute treatment of schizophrenia in adults and the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. It is pending approval for the treatment of schizophrenia and manic episodes associated with bipolar I disorder in Europe. Asenapine is administered as a sublingual formulation. To determine whether the pharmacokinetics of asenapine are impacted by placing the tablet buccally ('cheeking') or allowing the tablet to dissolve on the top of the tongue, pharmacokinetics were compared following buccal and supralingual administration versus sublingual administration. In this open-label, randomized, 3-way crossover trial, healthy men (n=36) receive... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3660402 Mon, 14 Jun 2010 23:00:00 +0100 3660402 http://www.medworm.com/index.php?rid=3660401&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.711 The objective of this study was to predict Rb (blood/plasma ratio) in humans using a simple method. Human and rat Rb and free fraction in plasma (fp) values were obtained from the literature. The ratio of total red blood cell concentration to the free concentration in plasma (Kb) was calculated using fp and Rb. Four methods were used for the prediction of Rb: (A) use of rat Rb; (B) use of Rb calculated from rat Kb and human fp; (C) correlation of human log ((1-fp)/fp) and human log Kb; and (D) correlation of log D with human log Kb. The Rb of 96 compounds in humans ranged from 0.52 to 2.00, with an average of 0.89. A significant correlation was observed among human log Kb, human log ((1-fp)/fp), and log D; however, no obvious correlation was observed among human Rb, human log ((1-fp)/fp), ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3660401 Mon, 14 Jun 2010 23:00:00 +0100 3660401 http://www.medworm.com/index.php?rid=3646097&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.717 The aim of our study was to investigate the effect of biochanin A on the accumulation and transport of mitoxantrone in breast cancer resistance protein (BCRP)-expressing normal cells and its impact on the pharmacokinetics (PK) and tissue distribution of mitoxantrone. In accumulation studies, the intracellular level of mitoxantrone was significantly increased in the presence of 2.5 or 25 µM of biochanin A in both murine and human BCRP-expressing Madin-Darby canine kidney (MDCK) cells, with no effect in corresponding MDCK/Mock cells. In bi-directional transport studies, the Papp,B-A value of mitoxantrone with biochanin A co-treatment was much lower (6.66±0.84×10-7 cm/s) than that in the absence of biochanin A (21.4±4.14×10-7 cm/s), indicating inhibition of Bcrp1-mediated efflux. To eval... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3646097 Wed, 09 Jun 2010 23:00:00 +0100 3646097 http://www.medworm.com/index.php?rid=3630802&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.712 In conclusion, rHuEPO exhibits a nonlinear PK with a time-dependent decrease of its CLTotal. During exposure, RET, RBC and Hb showed a tolerance effect. After exposure, the rebound was characterized for RET, RBC, but not Hb. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3630802 Fri, 04 Jun 2010 23:00:00 +0100 3630802 http://www.medworm.com/index.php?rid=3630803&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.715 Conclusions. Sotrastaurin did not alter the pharmacokinetics of cyclosporine, but cyclosporine increased sotrastaurin AUC up to 1.8-fold. The combined drugs elicited a significantly greater inhibition of T-cell activation and proliferation than sotrastaurin alone. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3630803 Thu, 03 Jun 2010 23:00:00 +0100 3630803 http://www.medworm.com/index.php?rid=3619180&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.716 In conclusion, these findings suggest that the enantioselectivity observed in vivo in the biodisposition of S-Lic and R-Lic is not dependent on their affinity to plasma proteins. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3619180 Tue, 01 Jun 2010 23:00:00 +0100 3619180 http://www.medworm.com/index.php?rid=3619179&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.714 The objective was to develop a population pharmacokinetic-pharmacodynamic model of caffeine's psychomotor effects in healthy, non-habitual users of caffeine. Twenty Chinese males each received a single dose of 250 mg of caffeine orally. Plasma concentrations of caffeine were determined at various times within 24 h after dosing. The subjects' psychomotor performance was evaluated before and at various times after dosing by a test battery consisting of oculomotor assessment (saccadic velocity) as well as the computerised Swedish Performance Evaluation System. Nonlinear mixed-effects modelling to analyse the pharmacokinetic-pharmacodynamic relationships was performed using NONMEM. Model robustness was assessed by a nonparametric bootstrap. The results showed that caffeine caused significant i... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3619179 Tue, 01 Jun 2010 23:00:00 +0100 3619179 http://www.medworm.com/index.php?rid=3619181&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.713 The pharmacokinetics of SP-8203, a potential protective agent for the treatment of cerebral infarction, were evaluated after its intravenous (10, 20 and 30 mg/kg) and oral (10, 20, 30 and 100 mg/kg) administration in rats. After the intravenous administration of SP-8203, the AUCs of SP-8203 were dose-dependent; the dose-normalized AUCs were significantly greater with increasing doses. After the oral administration of SP-8203, plasma concentrations of SP-8203 were much lower than those after intravenous administration. This could be due to considerable hepatic and intestinal metabolism and the high percent of the dose recovered from the gastrointestinal tract (including its contents and feces) at 24 h as unchanged drug. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3619181 Mon, 31 May 2010 23:00:00 +0100 3619181 http://www.medworm.com/index.php?rid=3535527&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.710 The present study explored the feasibility of a differential setup for the in situ perfusion technique with mesenteric cannulation in rats to assess drug interactions at the level of intestinal absorption. In contrast to the classic, parallel in situ perfusion setup, the differential approach aims to identify intestinal drug interactions in individual animals by exposing the perfused segment to a sequence of multiple conditions. First, the setup was validated by assessing the interaction between the P-glycoprotein (P-gp) inhibitor verapamil and the transport probes atenolol (paracellular transport), propranolol (transcellular) and talinolol (P-gp mediated efflux). While transport of atenolol and propranolol remained constant for the total perfusion time (2 h), a verapamil-induced increase ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3535527 Wed, 05 May 2010 23:00:00 +0100 3535527 http://www.medworm.com/index.php?rid=3488301&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.709 Conclusion. The microemulsion and macroemulsion propofol formulations had similar pharmacokinetics and did not modify thromboelastographic parameters in swine. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3488301 Tue, 20 Apr 2010 23:00:00 +0100 3488301 http://www.medworm.com/index.php?rid=3450856&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.705 Paclitaxel is a substrate of the efflux transporters such as P-glycoprotein, and is mainly metabolized by the liver. Schisandrol B (Sch B), one of the active components in Schisandra, has been reported to be able to inhibit the activity of P-gp and CYP3A. It might be possible that Sch B would alter the pharmacokinetic behavior of paclitaxel. Therefore, the purpose of this study was to investigate the effect of Sch B on the pharmacokinetics of paclitaxel administered orally and intravenously in rats. Paclitaxel were administered to rats orally (30 mg/kg) or intravenously (0.5 mg/kg) with or without the concomitant administration of Sch B (10 or 25 mg/kg). Oral pharmacokinetic parameters of paclitaxel were significantly altered when pretreated with Sch B. There were significant increases in ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3450856 Thu, 08 Apr 2010 23:00:00 +0100 3450856 http://www.medworm.com/index.php?rid=3450860&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.706 Glyburide (GLB) is a widely used oral sulfonylurea for the treatment of gestational diabetes. The therapeutic use of GLB is often complicated by a substantial inter-individual variability in the pharmacokinetics and pharmacodynamics of the drug in human populations, which might be caused by inter-individual variations in factors such as GLB metabolism. Therefore, there has been a continued interest in identifying human cytochrome P450 (CYP) isoforms that play a major role in the metabolism of GLB. However, contrasting data are available in the present literature in this regard. The present study systematically investigated the contributions of various human CYP isoforms (CYP3A4, CYP3A5, CYP2C8, CYP2C9 and CYP2C19) to in vitro metabolism of GLB. GLB depletion and metabolite formation in hum... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3450860 Wed, 07 Apr 2010 23:00:00 +0100 3450860 http://www.medworm.com/index.php?rid=3450859&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.708 In this report, the utility of a commonly used interspecies scaling method to predict the systemic clearance (CL) of therapeutic proteins in humans was evaluated. Based on analysis of a pharmacokinetic data set of 34 therapeutic proteins, including 12 monoclonal antibodies (mAbs) and Fc fusion proteins, human CL can generally be predicted reasonably well with simple allometric scaling and a fixed exponent of 0.8:[sim]95% of the cases predicted values within 2-fold of the observed values when using CL data from multiple species, or[sim]90% simply using CL from monkeys. Specific to mAbs/Fc fusion proteins, scaling from monkey CL using a fixed exponent of 0.8 gave an excellent prediction; all predicted CL values were within 2-fold of the corresponding observed values. Compared with the simple... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3450859 Wed, 07 Apr 2010 23:00:00 +0100 3450859 http://www.medworm.com/index.php?rid=3450858&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.707 Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood-brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [3H]naloxone exhibited saturability in a concentration-dependent manner (concentration range 0.5 µM to 15 mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier-mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, Kt, was 2.99±0.71 mM; the maximum uptake rate, Jmax, was 0.477±0.083 µmol/min/g b... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3450858 Wed, 07 Apr 2010 23:00:00 +0100 3450858 http://www.medworm.com/index.php?rid=3450857&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.704 Interactions are expected between transporters and enzymes that compete for the substrate within the cell, and controversy exists for data interpretation on the interplay between transporters and enzymes. In the Caco-2 cell monolayer, the increase in mean residence time (MRT) of drug accompanying increased secretion has been construed as the reason for increased metabolism, whereas others hold an opposite view that increased secretion would evoke decreased metabolism in this closed system. A catenary Caco-2 cell model was used to simulate the effects of altered secretion on metabolism, estimated as the fraction of dose metabolized (fmet) or the extraction ratio (ER). The simulations showed that both fmet and ER varied inversely with the transporter-mediated intrinsic clearance for apical s... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3450857 Wed, 07 Apr 2010 23:00:00 +0100 3450857 http://www.medworm.com/index.php?rid=3375702&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.701 In conclusion, several HIV PI showed substantial ABCC2 inhibition, which, combined with the effects of PI on other hepatobiliary disposition mechanisms, will determine the clinical relevance of these in vitro interaction data. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3375702 Thu, 18 Mar 2010 00:00:00 +0100 3375702 http://www.medworm.com/index.php?rid=3375704&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.703 This study investigated the effects of orally administered morin (1.0, 2.5 and 5.0 mg kg-1), on the pharmacokinetics of orally (10 mg kg-1) and intravenously (1.0 mg kg-1) administered talinolol in rats. In the presence of morin, the pharmacokinetic parameters of talinolol were significantly altered in the oral group but not in the intravenous group. The presence of 2.5 and 5.0 mg kg-1 of morin significantly increased (1.8-2.0 fold, p (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3375704 Wed, 17 Mar 2010 00:00:00 +0100 3375704 http://www.medworm.com/index.php?rid=3375703&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.702 The pulmonary route is an alternative route of administration for the systemic delivery of peptide and proteins with short-half lives. A long-acting formulation of insulin was prepared by encapsulation of protein into respirable, biodegradable microcapsules prepared by an oil in oil emulsification/solvent evaporation method. Insulin-loaded PLGA microcapsules prepared as a dry powder inhaler formulation were administered via the pulmonary route to diabetic rats and serum insulin and glucose concentrations were monitored. Control treatments consisted of respirable spray-dried insulin (RSDI) powder administered by intratracheal insufflation, insulin-loaded PLGA microcapsules and NPH (long-acting) insulin administered by subcutaneous (SC) administration. Pharmacokinetic analysis demonstrated t... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3375703 Wed, 17 Mar 2010 00:00:00 +0100 3375703 http://www.medworm.com/index.php?rid=3351806&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.699 In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3351806 Thu, 11 Mar 2010 00:00:00 +0100 3351806 http://www.medworm.com/index.php?rid=3344000&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.700 In conclusion, the ability of system-specific parameters to predict HbA1c provides a tool to predict the expected efficacy profile from abbreviated dose-finding trials. To be commercially viable, new drugs should improve [Delta]HbA1c by about 0.8% or more and possess safety profiles similar to newer anti-diabetic agents. Thus, this study proposes a suite of simple yet powerful tools to guide type-2-diabetes drug development. Copyright © 2010 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3344000 Tue, 09 Mar 2010 00:00:00 +0100 3344000 http://www.medworm.com/index.php?rid=3264150&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.697 The rapid achievement of efficacious exposure to sirolimus (SRL) after renal transplantation is crucial. However, there is high unpredictability in the dose to exposure relationship. Part of the variation is related to patients originating from subpopulations of fast or slow metabolizers via the CYP3A5*1/*3 genotype. The probability of achieving therapeutic SRL blood concentrations for each subpopulation under two equal-intensity increasing-frequency protocols after the start of treatment was explored with Monte Carlo simulation. The population pharmacokinetic model and inter-patient variability distributions of Djebli et al. (DRH2006) were sampled. They developed a base and final model with a genotype covariate for CL/F in patients receiving calcineurin inhibitor (CNI)-free therapy with S... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3264150 Fri, 12 Feb 2010 00:00:00 +0100 3264150 http://www.medworm.com/index.php?rid=3249309&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.698 The purpose of this study was to formulate a drug-in-adhesive (DIA) transdermal patch containing letrozole, a third generation aromatase inhibitor for the treatment of breast cancer, using pressure-sensitive-adhesives (PSAs) and to evaluate the percutaneous penetration and pharmacokinetics of letrozole after transdermal administration, compared with that for the oral route. The formulation factors for such a patch, including the PSAs, enhancers and amount of drug loaded were investigated. Among the tested preparations, the formulation with DURO-TAK 87-4098, Azone and propylene glycol showed the highest letrozole permeation. The pharmacokinetic characteristics of an optimized DIA patch containing letrozole were determined using rats, while orally administered letrozole in solution was used ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3249309 Mon, 08 Feb 2010 00:00:00 +0100 3249309 http://www.medworm.com/index.php?rid=3165165&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.696 The binding of sulfacetamide sodium (SAS) to bovine serum albumin (BSA) was investigated by spectroscopic methods, namely fluorescence, FT-IR and UV-vis absorption spectral studies. The binding parameters were evaluated by a fluorescence quenching method. The thermodynamic parameters, [Delta]H0, [Delta]S0and [Delta]G0 were observed to be -49.03 k J mol-1, -99.9 J K-1 mol-1 and -18.96 k J mol-1, respectively. These indicated that the hydrogen bonding and weak van der Waals forces played major roles in the interaction. Based on Förster's theory of non-radiation energy transfer, the binding average distance, r, between the donor (BSA) and acceptor (SAS) was evaluated and found to be 3.72 nm. The spectral results showed that binding of SAS to BSA induced conformational changes in BSA. The eff... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3165165 Wed, 13 Jan 2010 00:00:00 +0100 3165165 http://www.medworm.com/index.php?rid=4005402&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.727 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=4005402 Fri, 01 Jan 2010 00:00:00 +0100 4005402 http://www.medworm.com/index.php?rid=3970423&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.726 Abstract (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3970423 Fri, 01 Jan 2010 00:00:00 +0100 3970423 http://www.medworm.com/index.php?rid=3076916&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.695 In conclusion, the present data support the model that the sustained drug release property of 7:1 MA/[beta]-CD composition resulted in the prolongation of MA absorption by the oral route and, consequently, in the increase of the drug mean residence time in serum. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3076916 Fri, 11 Dec 2009 00:00:00 +0100 3076916 http://www.medworm.com/index.php?rid=3072879&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.694 1[alpha],25-Dihydroxyvitamin D3 (1,25(OH)2D3), the natural ligand of the vitamin D receptor (VDR), was found to regulate bile acid related transporters and enzymes directly and indirectly in the rat intestine and liver in vivo. The kidney is another VDR-rich target organ in which VDR regulation on xenobiotic transporters and enzymes is ill-defined. Hence, changes in protein and mRNA expression of nuclear receptors, transporters and enzymes of the rat intestine and kidney in response to 1,25(OH)2D3 treatment (0 to 2.56 nmol/kg/day intraperitoneally in corn oil for 4 days) were studied. In the intestine, protein and not mRNA levels of Mrp2, Mrp3, Mrp4 and PepT1 in the duodenum and proximal jejunum were induced, whereas Oat1 and Oat3 mRNA were decreased in the ileum after 1,25(OH)2D3 treatmen... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3072879 Thu, 10 Dec 2009 00:00:00 +0100 3072879 http://www.medworm.com/index.php?rid=3041181&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.693 Our understanding of the mechanisms behind inter- and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with or... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=3041181 Tue, 01 Dec 2009 00:00:00 +0100 3041181 http://www.medworm.com/index.php?rid=2978840&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.692 In this study, in vivo rat biliary excretion of drug-like molecules was measured using bile duct cannulated rats. Literature biliary excretion data with similar experimental conditions were collected. A predictive quantitative structure-pharmacokinetic relationship (QSPR) model was developed using genetic algorithm guided principal component regression analysis and 2D molecular descriptors. In the derived model, hydrophobicity expressed with calculated distribution coefficients (cLogD) is the most important molecular property correlating biliary excretion. The derived model has been validated using literature data, and should be useful in estimating biliary excretion potentials of molecules in drug discovery. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disp... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2978840 Wed, 11 Nov 2009 00:00:00 +0100 2978840 http://www.medworm.com/index.php?rid=2941003&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.691 An in vitro-in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC-MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin®. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2941003 Fri, 30 Oct 2009 00:00:00 +0100 2941003 http://www.medworm.com/index.php?rid=2932376&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.689 The effect of obesity induced by a high-fat diet on the pharmacokinetics (PK) of nelfinavir (NFV) was investigated, focusing on the change of distribution and elimination caused by dyslipidemia and hepatic steatosis.The plasma unbound fraction (fu) of NFV in obese rats (0.61±0.03%) was significantly lower than in the control (1.10±0.09%), caused by increasing the plasma triglyceride-rich lipoprotein level. After intravenous (i.v.) administration of NFV, the marked decrease of the distribution volume and slower total clearance (39.5% and 69.1% of the control, respectively) caused by the lower fu were the main reasons for the significantly higher area under the blood concentration versus time curve (AUC) in obese rats (145.3% of the control). The absorption of NFV after intraduodenal (i.d.... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2932376 Wed, 28 Oct 2009 00:00:00 +0100 2932376 http://www.medworm.com/index.php?rid=2928583&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.690 The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F-ara-AMP) were evaluated in adult patients with B-cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25 mg/m2, n=14) or oral (40 mg/m2, n=42) 2F-ara-AMP. Plasma concentrations of drug and metabolites and digital 12-lead ECGs were monitored for 23 h after dosing. The dephosphorylated product fludarabine (2F-ara-A) was the principal metabolite present in the systemic circulation. Mean (±SD) elimination half-life did not differ significantly between IV and oral dosage groups (11.3±4.0 vs 9.7±2.0 h, p=0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F-ara-Hx. Estimated mean ora... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2928583 Tue, 27 Oct 2009 00:00:00 +0100 2928583 http://www.medworm.com/index.php?rid=2881721&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.688 The plasma concentration profile of lamotrigine was predicted from the dissolution test data of the modified release 100 mg lamotrigine tablet by applying the in vitro-in vivo correlation (IVIVC). Three different release formulations (L-1, L-2 and L-3) and its profiles of in vitro data were generated in different dissolution media. Pharmacokinetics evaluation of these formulations was carried out in 12 healthy volunteers. In vitro-in vivo correlation was established from the generated dissolution and bioavailability data. A good correlation between the percentages dissolved vs absorbed (r2>0.989) was obtained using level A correlation. Evaluation of the internal predictability of level A correlation was calculated in terms of percent prediction error, which was found to be below 15%. Copyr... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2881721 Sun, 11 Oct 2009 23:00:00 +0100 2881721 http://www.medworm.com/index.php?rid=2873492&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.681 Carnitine/organic cation transporter 2 (OCTN2) recognizes various cationic compounds as substrates in vitro, but information on its pharmacokinetic role in vivo is quite limited. This paper demonstrates altered tissue distribution of the OCTN2 substrate pyrilamine in juvenile visceral steatosis (jvs) mice, which have a hereditary defect of the octn2 gene. At 30 min after intravenous injection of pyrilamine, the tissue-to-plasma concentration ratio (Kp) in the heart and pancreas was higher, whereas the Kp in kidney and testis was lower in jvs mice compared with wild-type mice. Pyrilamine transport studies in isolated heart slices confirmed higher accumulation, together with lower efflux, of pyrilamine in the heart of jvs mice. The higher accumulation in heart slices of jvs mice was abolishe... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2873492 Thu, 08 Oct 2009 23:00:00 +0100 2873492 http://www.medworm.com/index.php?rid=2848191&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.683 Acipimox is an analog of nicotinic acid and is indicated for the treatment of dyslipidemia. It is also believed to improve glucose control by enhancing insulin sensitivity. The purpose of this study was to direct modified release (MR) formulation strategy by comparing the bioavailability of two forms of acipimox (free acid and sodium salt) from the distal small bowel (DSB) and colon with an immediate release formulation. Two parallel groups of healthy volunteers completed an open label, non-randomized, three-way crossover study. The rate and extent of acipimox absorption was highest following administration of the immediate release capsules, and was not influenced by the form of the drug administered. Following administration to the DSB, the relative bioavailability was approximately 52% a... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2848191 Wed, 30 Sep 2009 23:00:00 +0100 2848191 http://www.medworm.com/index.php?rid=2844205&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.687 In conclusion, intraintestinally administered itraconazole dramatically increased the AUC of everolimus delivered intraintestinally by inhibiting the intestinal first-pass extraction of this drug. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2844205 Tue, 29 Sep 2009 23:00:00 +0100 2844205 http://www.medworm.com/index.php?rid=2829644&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.686 The aim of this study was to investigate the pharmacokinetic behavior of huperzine A (Hup A) in plasma and cerebrospinal fluid (CSF) after intranasal administration (0.5 mg/kg) in male Sprague-Dawley rats. A pharmacokinetic study of intravenous Hup A (0.5 mg/kg) was also performed. The concentrations of Hup A in the biological samples were measured by high performance liquid chromatography-mass spectrometry. Blood samples were taken from the tail vein and CSF was sampled by cisternal puncture using a stereotaxic frame. The contribution of the olfactory pathway to the uptake of Hup A into CSF was determined by comparing the AUCCSF/AUCplasma ratios after intranasal and intravenous administration. The AUC ratios of intranasal to intravenous administration in CSF and plasma were 104% and 118%,... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2829644 Thu, 24 Sep 2009 23:00:00 +0100 2829644 http://www.medworm.com/index.php?rid=2816087&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.676 In conclusion, the study showed that the concentration-dependent binding of linagliptin to its target DPP-4 has a major impact on the plasma pharmacokinetics of linagliptin. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2816087 Mon, 21 Sep 2009 23:00:00 +0100 2816087 http://www.medworm.com/index.php?rid=2805600&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.684 This study for the first time produced detailed comparative findings for uptake profiles of metformin and phenformin in human hepatocytes and hOCT1 expressing oocytes. It is considered that hOCT1 may not be the only key factor that determines the frequency of metformin and phenformin toxicity, considering the major contribution of this transporter to the total hepatic uptake and comparable width of their therapeutic concentrations. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2805600 Thu, 17 Sep 2009 23:00:00 +0100 2805600 http://www.medworm.com/index.php?rid=2794394&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.685 It has been reported that chlorzoxazone (CZX) was primarily metabolized via hepatic Cyp2e1 to form 6-hydroxychlorzoxazone (OH-CZX) in rats, and the activity of aniline hydroxylase (a Cyp2e1 marker) in the liver was significantly decreased in rats at 24 h after pretreatment with lipopolysaccharide derived from Klebsiella pneumoniae (24 h KPLPS rats), whereas the levels were not changed at 2 h and 96 h in the KPLPS rats. Thus, the time-dependent pharmacokinetic parameters of CZX and OH-CZX were evaluated after the intravenous administration of CZX (20 mg/kg) to control rats, and the 2 h, 24 h and 96 h KPLPS rats along with the time-dependent changes in the protein expression of hepatic Cyp2e1. After the intravenous administration of CZX to 24 h KPLPS rats, the AUC0-2 h of OH-CZX and AUCOH-CZ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2794394 Mon, 14 Sep 2009 23:00:00 +0100 2794394 http://www.medworm.com/index.php?rid=2791277&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.682 1[alpha],25-Dihydroxyvitamin D3 (1,25(OH)2D3), a natural ligand of the vitamin D receptor (VDR), was found to increase the rat ileal Asbt and bile acid absorption. The effects of VDR, whose expression is low in liver, on hepatic transporters and enzymes are unknown. Protein and mRNA levels of target genes in the small intestine, colon and liver after intraperitoneal dosing of 1,25(OH)2D3 (0-2.56 nmol/kg/day for 4 days) to the rat were determined by Western blotting and qPCR, respectively. The 1,25(OH)2D3 treatment increased total Cyp3a protein and Cyp3a1 mRNA expressions in the proximal small intestine, and the short heterodimer partner (SHP), the fibroblast growth factor 15 (FGF15), organic solute transporter (Ost[alpha] and Ost[beta]) mRNA and Asbt protein expressions in the ileum. About... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2791277 Sun, 13 Sep 2009 23:00:00 +0100 2791277 http://www.medworm.com/index.php?rid=2779870&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.675 The purpose of this study was to compare the expression profiles of drug-metabolizing enzymes in the intestine of mouse, rat and human. Total RNA was isolated from the duodenum and the mRNA expression was measured using Affymetrix GeneChip oligonucleotide arrays. Detected genes from the intestine of mouse, rat and human were ca. 60% of 22690 sequences, 40% of 8739 and 47% of 12559, respectively. Total genes of metabolizing enzymes subjected in this study were 95, 33 and 68 genes in mouse, rat and human, respectively. Of phase I enzymes, the mouse exhibited abundant gene expressions for Cyp3a25, Cyp4v3, Cyp2d26, followed by Cyp2b20, Cyp2c65 and Cyp4f14, whereas, the rat showed higher expression profiles of Cyp3a9, Cyp2b19, Cyp4f1, Cyp17a1, Cyp2d18, Cyp27a1 and Cyp4f6. However, the highly ex... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2779870 Wed, 09 Sep 2009 23:00:00 +0100 2779870 http://www.medworm.com/index.php?rid=2779871&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.678 The purpose of present study was to develop a population pharmacokinetic model of high dose methotrexate (HD-MTX) infusion in patients with lymphoid malignancy, to investigate the biological and clinical covariates related to the drug distribution and elimination. It is also the purpose to propose a limited sampling strategy (LSS) for the estimation of the time above the threshold (0.2 µmol·L-1). A total 82 patients with lymphoid malignancy were involved in the study. A pharmacokinetic model was developed using nonlinear mixed-effect model. The influence of demographic characteristics, biological factors, and concurrent administration were investigated. The final predictive performance was validated by bootstrap and cross-validation. Bayesian estimation was evaluated. The pharmacokinetic... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2779871 Tue, 08 Sep 2009 23:00:00 +0100 2779871 http://www.medworm.com/index.php?rid=2763557&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.672 IVIVC (in vitro in vivo correlation) methods may support approving a change in formulation of a drug using only in vitro dissolution data without additional bioequivalence trials in human subjects. Most current IVIVC methods express the in vivo plasma concentration of a drug formulation as a function of the cumulative in vivo absorption. The absorption is not directly observable, so is estimated by the cumulative dissolution of the drug formulation in in vitro dissolution trials. The calculations conventionally entail the complex and potentially unstable mathematical operations of convolution and deconvolution, or approximations aimed at omitting their need. This paper describes, and illustrates with data on a controlled-release formulation, a Bayesian approach to evaluating IVIVC that doe... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2763557 Thu, 03 Sep 2009 23:00:00 +0100 2763557 http://www.medworm.com/index.php?rid=2749019&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.679 It was reported previously that specific levofloxacin uptake in Caco-2 cells was inhibited by nicotine, enalapril, L-carnitine and fexofenadine. The aim of the present study was to characterize the cellular uptake of levofloxacin using another human intestinal cell line, LS180. Levofloxacin uptake in LS180 cells was temperature-dependent and optimal at neutral pH, but was Na+-independent. The rank order of inhibitory effects of the four compounds on [14C] levofloxacin uptake in LS180 cells was nicotine>enalapril>L-carnitine>fexofenadine, which is consistent with that in Caco-2 cells. The mRNA levels of OATP1A2, 1B1, 1B3 and 2B1 in LS180 cells were markedly different from those in Caco-2 cells, and OATP substrates/inhibitors had no systematic effect on the levofloxacin uptake. The mRNA leve... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2749019 Mon, 31 Aug 2009 23:00:00 +0100 2749019 http://www.medworm.com/index.php?rid=2749020&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.680 The nuclear transcription factor E2-related factor 2 (Nrf2) has been shown to play pivotal roles in preventing xenobiotic-related toxicity and carcinogen-induced carcinogenesis. These protective roles of Nrf2 have been attributed in part to its involvement in the induction of Phase II drug conjugation/detoxification enzymes as well as antioxidant enzymes through the Nrf2-antioxidant response element (ARE) signaling pathways. This review summarizes the current research status of the identification of Nrf2-regulated drug metabolism enzymes (DMEs), especially Phase II DMEs, and Phase III drug transporters. In addition, the molecular mechanisms underlying the coordinated regulation of Phase II DMEs and Phase III transporters will also be discussed based on findings published in the literature.... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2749020 Sun, 30 Aug 2009 23:00:00 +0100 2749020 http://www.medworm.com/index.php?rid=2746528&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.677 The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (Km and Vmax), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered kaempferol intravenously (i.v.) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro-intestinal first-pass effects were observed by collecting portal blood after oral administration of 100 mg/kg kaempferol. P... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2746528 Sun, 30 Aug 2009 23:00:00 +0100 2746528 http://www.medworm.com/index.php?rid=2704659&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.674 Radix Scutellariae (RS) and Coptis Chinensis (CC) are the most popular components in traditional Chinese medicine prescriptions. Flavonoids are the main effective ingredients in RS and berberine is the main effective ingredient in CC. The aim of this study was to determine the influence of CC on the pharmacokinetics of flavonoids following the administration of RS in rats and to investigate the effects of CC on the pharmacokinetic mechanism. Rats were administered RS or RS+CC by intragastric gavage (ig). Plasma concentrations of baicalin (baicalein 7-glucuronide) and wogonoside (wogonin 7-glucuronide) were measured by HPLC. Pharmacokinetic parameters were calculated from the plasma concentration time curve. The effect of CC on the metabolism of flavonoids in RS by rat intestinal flora was ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2704659 Sun, 16 Aug 2009 23:00:00 +0100 2704659 http://www.medworm.com/index.php?rid=2704660&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.673 In this study, the biochemical stability of Cuc E was investigated in vitro by reverse-phase high performance liquid chromatography. The hydrolysis rate in acidic and alkaline solutions, and in enzymatic conditions in human plasma and in purified plasma esterase solutions of butyrylcholinesterase and albumin, was compared with that measured in phosphate buffer saline (pH 7.4).Cuc E hydrolysis was detected in all the in vitro tests, but the extent of hydrolysis varied according to the different enzymatic and non-enzymatic conditions. A remarkable rapid hydrolysis of Cuc E was detected in acidic and alkaline solutions. A significant rate of hydrolysis of Cuc E was monitored in human plasma and was associated with the detection of Cuc I.The stability of Cuc E was greatly enhanced in the prese... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2704660 Sat, 15 Aug 2009 23:00:00 +0100 2704660 http://www.medworm.com/index.php?rid=2651491&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.670 The suitability of various media to forecast the solubility of ketoconazole and dipyridamole in the fed stomach at various periods after meal administration was evaluated. Solubilities were measured with the shake-flask method in gastric fluids aspirated 30, 60 and 120 min after administration of 500 ml Ensure plus® to healthy fasted adults, in three sets of simulated gastric fluids based on milk, and in simple aqueous buffered media. Simple aqueous buffered media vastly underestimated the intragastric solubility of model compounds in the fed state. When using undigested milk-based media, the solubilities of model compounds in aspirates were also underestimated by a factor of 2.5-27. Solubility in milk digested with pepsin was useful for estimating the intragastric solubility of ketoconaz... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2651491 Wed, 29 Jul 2009 23:00:00 +0100 2651491 http://www.medworm.com/index.php?rid=2646974&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.671 The purpose of this study was to evaluate the mechanisms responsible for the pharmacokinetic variability of bosentan utilizing rats with liver dysfunction induced by 7-day bile duct ligation (BDL). Bosentan was administered intravenously at a constant infusion rate (I) of 24, 40 or 60 µg/min/kg. The blood bosentan concentration (BBC) following infusion was measured by HPLC, and apparent clearance (CL) of the drug was estimated as I/BBC. The CL values in normal rats were 30.5 and 19.3 ml/min/kg at infusion rates of 24 and 60 µg/min/kg, respectively, suggesting non-linear pharmacokinetics of bosentan. The BBC in BDL rats was much higher than that in normal rats, and the CL values in BDL rats were 3.80 and 3.08 ml/min/kg at infusion rates of 24 and 60 µg/min/kg, respectively. The CL value ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2646974 Tue, 28 Jul 2009 23:00:00 +0100 2646974 http://www.medworm.com/index.php?rid=2642648&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.669 The pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, after intravenous (5, 10, 20 and 50 mg/kg) and oral (10, 20 and 50 mg/kg) administration of mirodenafil, and the first-pass effect of mirodenafil after intravenous, oral, intraportal, intragastric and intraduodenal (20 mg/kg) administration of mirodenafil were evaluated in rats. The pharmacokinetics of mirodenafil and SK3541 were dose-dependent after both intravenous and oral administration of mirodenafil due to the saturable hepatic metabolism of mirodenafil. After oral administration of mirodenafil, approximately 2.59% of the oral dose was not absorbed, the F value was approximately 29.4%, and the hepatic and gastrointestinal first-pass effects of mirodenafil were approximately 21.4% and 54.3% of the oral dos... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2642648 Mon, 27 Jul 2009 23:00:00 +0100 2642648 http://www.medworm.com/index.php?rid=2623262&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.668 Isothiocyanates, a class of anti-cancer agents, are derived from cruciferous vegetables such as broccoli, cabbage and watercress, and have demonstrated chemopreventive activity in a number of cancer models and epidemiologic studies. Due to public interest in cancer prevention and alternative therapies in cancer, the consumption of herbal supplements and vegetables containing these compounds is widespread and increasing. Isothiocyanates interact with ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein, MRP1, MRP2 and BCRP, and may influence the pharmacokinetics of substrates of these transporters. This review discusses the pharmacokinetic properties of isothiocyanates, their interactions with ABC transporters, and presents some data describing the potential for isothiocyan... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2623262 Tue, 21 Jul 2009 23:00:00 +0100 2623262 http://www.medworm.com/index.php?rid=2589696&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.658 In conclusion, this study shows that it is possible to generate a reasonable prediction of skin pharmacokinetics from any plasma level once a careful characterization of the transfer process between plasma and skin has been made. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2589696 Fri, 10 Jul 2009 23:00:00 +0100 2589696 http://www.medworm.com/index.php?rid=2582033&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.667 In this study, the contribution of hepatic CYP2C11 and intestinal CYP1A protein to the metabolism and the pharmacokinetic parameters of ipriflavone were examined after intravenous (20 mg/kg) and oral (200 mg/kg) administration to male Sprague-Dawley (control) rats and NARs. There was no change in the protein expression of hepatic CYP2C11. By contrast, CYP1A protein of the intestine increased by almost 100%. After the intravenous administration of ipriflavone to NARs, the Clnr and AUC were unchanged, suggesting that the contribution of the increase in protein expression and mRNA level of hepatic CYP1A2 to hepatic metabolism of the drug in NARs seemed to be almost negligible. However, after the oral administration of ipriflavone to NARs, the AUC was significantly lower than that in the contr... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2582033 Wed, 08 Jul 2009 23:00:00 +0100 2582033 http://www.medworm.com/index.php?rid=2515970&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.665 Aim. To compare in vitro metabolism rates for artemisinin and the CYP2B6 substrates, bupropion, propofol and efavirenz in human liver microsomes.Methods. Rate constants of artemisinin, bupropion, propofol and efavirenz metabolism by human liver microsomes from a panel of 12 donors, with different levels of CYP2B6 activity, were estimated in WinNonlin. Correlations between the metabolic rate constant for artemisinin and the other CYP2B6 substrates were examined.Results. Artemisinin and propofol depletion data in human liver microsomes were described by first order kinetic models. For bupropion and efavirenz, metabolite formation data were incorporated in the model. Rate constants varied considerably for all substrates. There was a high degree of correlation of rate constants between substra... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2515970 Wed, 24 Jun 2009 23:00:00 +0100 2515970 http://www.medworm.com/index.php?rid=2515969&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.664 The intestinal absorptive characteristics and the efflux mechanisms of candesartan (CDS), a novel angiotensin II type 1 receptor blocker, were investigated. The Caco-2 cells were used as models of the intestinal mucosa to assess uptake and transport of CDS. The determination of CDS was performed by HPLC-Flu. In the Caco-2 cells, the uptake and absorptive transport of CDS were pH-independent (in the pH range 6.0-8.0). Passive membrane diffusion dominates the absorptive transport behavior of CDS across Caco-2 cells, while secretory transport was a concentration-dependent and saturable process. In the presence of cyclosporin A and verapamil, potent inhibitors of P-glycoprotein (P-gp), the Pratio decreased from 3.8 to 2.3 and 1.8, respectively, and permeation of apical to basolateral was enhan... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2515969 Wed, 24 Jun 2009 23:00:00 +0100 2515969 http://www.medworm.com/index.php?rid=2515968&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.663 This study suggest that, apart from FXR ligands, the OST[alpha] and OST[beta] genes are also regulated by VDR and GR ligands and not by PXR ligands. This study show that VDR ligands exerted different effects on OST[alpha]-OST[beta] in the rat and human intestine and liver compared with other nuclear receptors, FXR, PXR, and GR, pointing to species- and organ-specific differences in the regulation of OST[alpha]-OST[beta] genes. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2515968 Wed, 24 Jun 2009 23:00:00 +0100 2515968 http://www.medworm.com/index.php?rid=2515967&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.662 This study investigated whether saturable binding of BI 1356 to its target DPP-4 occurs in tissues and whether drug accumulation occurs at these sites in vivo. In order to test these hypotheses, the tissue distribution of BI 1356 was determined in wild-type and DPP-4 deficient rats at different dose levels by means of whole body autoradiography and measurement of tissue radioactivity concentrations after single i.v. dosing of [14C]-radio labeled BI 1356. The accumulation behavior of drug-related radioactivity in tissues was further explored in an oral repeat dose study. Tissue levels of [14C]BI 1356 related radioactivity were markedly lower in all investigated tissues of the DPP-4 deficient rats and the difference of the dose-dependent increase of radioactivity tissue levels between both r... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2515967 Wed, 24 Jun 2009 23:00:00 +0100 2515967 http://www.medworm.com/index.php?rid=2489019&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.666 Sepsis has been reported to increase the volume of distribution of gentamicin in neonates. To determine whether this was caused by the use of intravenous volume expanders a retrospective nested case-control study was performed comparing confirmed septic neonates with non-septic controls. Data were collected on intravenous administration of 0.45% saline/10% dextrose, 0.45% saline/5% dextrose, 0.9% normal saline, red blood cells, platelets, immunoglobulin (Intragam P) and albumin. A population pharmacokinetic analysis was performed using NONMEM for 116 neonates (29 confirmed septic) from which 363 gentamicin serum concentrations were available. The final covariate model was CL=0.097×(current weight/2)1.3×(postnatal age/7)0.29 and V=1.07×(current weight/2)0.8+(confirmed sepsis)×0.13. The ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2489019 Wed, 24 Jun 2009 23:00:00 +0100 2489019 http://www.medworm.com/index.php?rid=2489020&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.657 The pharmacokinetic profiles of caffeic acid phenethyl ester (CAPE) and its catechol-ring fluorinated derivative (FCAPE) were determined in rats after intravenous administration of 5, 10 or 20 mg/kg for CAPE and 20 mg/kg for FCAPE, respectively. The plasma concentrations of CAPE and FCAPE were measured using a validated liquid chromatography tandem mass spectrometric method. The pharmacokinetic parameters were estimated using non compartmental analysis (NCA) and biexponential fit. The results showed that the area under the plasma concentration-time curve for CAPE treatment increased in a proportion greater than the increase in dose from 5 to 20 mg/kg of CAPE. Total body clearance values for CAPE ranged from 42.1 to 172 ml/min/kg (NCA) and decreased with the increasing dose of CAPE. Similar... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2489020 Tue, 16 Jun 2009 23:00:00 +0100 2489020 http://www.medworm.com/index.php?rid=2437726&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.656 The objectives of this study were to characterize the pharmacokinetics of sertindole and its active metabolite dehydrosertindole in rats and to evaluate the central modulatory and behavioural pharmacodynamics including a competitive interaction model between the compounds. Following oral administration of sertindole or dehydrosertindole, the plasma concentration-time courses were determined in conjunction with striatal dopamine D2 receptor binding. In addition, the behavioural effects were recorded in the conditioned avoidance response (CAR) paradigm. A one-compartment model with Michaelis-Menten elimination best described the pharmacokinetics of sertindole. Formation of dehydrosertindole was incorporated into the pharmacokinetic model and exhibited first-order elimination. PK/PD modelling... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2437726 Wed, 27 May 2009 04:00:00 +0100 2437726 http://www.medworm.com/index.php?rid=2407559&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.655 This study examined the usefulness of Mexican hairless pigs for in vivo pharmacokinetic study, especially the drug concentration in the tissues. A ketoprofen patch was applied on the back of Mexican hairless pigs for 24 h, followed by sequential collection of blood specimens from 0 to 36 h (n=3). Also, the skin, subcutaneous fat, fascia and muscle from the center of the site of application were excised at 12 h after the application (n=4). Ketoprofen was first detected in the plasma at 8 h, the concentration increasing up to 24 h; the plasma concentration began to decrease after the removal of the ketoprofen patch. Ketoprofen concentrations in the tissues decreased with increasing depth of the tissues, but the values in the deep muscles, being the lowest among the tissues examined, were sti... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2407559 Fri, 15 May 2009 04:00:00 +0100 2407559 http://www.medworm.com/index.php?rid=2307884&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.654 Methotrexate is used widely in the pharmacotherapy of juvenile idiopathic arthritis. Polyglutamates of methotrexate are active metabolites which accumulate in cells including erythrocytes. Their intracellular concentration may reflect methotrexate bioavailability and, at the same time, may serve as a bioindicator for optimization of methotrexate therapy and drug monitoring. Therefore, a simple and selective isocratic reversed phase chromatographic method with fluorescence detection (excitation/emission wavelengths of 370/463 nm) was developed which quantifies the sum of all methotrexate polyglutamates in erythrocytes as methotrexate after their enzymatic conversion with [gamma]-glutamylhydrolase. Separation was carried out on a Phenomenex GEMINI C18 column using a mobile phase flowing at a... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2307884 Wed, 25 Mar 2009 04:00:00 +0100 2307884 http://www.medworm.com/index.php?rid=2307883&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.653 L-Citrulline has diagnostic potential for renal function, because its plasma concentration increases with the progression of renal failure. Although L-citrulline extracted by glomerular filtration in kidney is mostly reabsorbed, the mechanism involved is not clearly understood. The present study was designed to characterize L-citrulline transport across the apical membranes of renal epithelial tubular cells, using primary-cultured rat renal proximal tubular cells, as well as the human kidney proximal tubular cell line HK-2. L-Citrulline was transported in a Na+-dependent manner from the apical side of both cell types cultured on permeable supports with a microporous membrane. Kinetic analysis indicated that the transport involves two distinct Na+-dependent saturable systems and one Na+-ind... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2307883 Wed, 25 Mar 2009 04:00:00 +0100 2307883 http://www.medworm.com/index.php?rid=2269824&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.652 The objective of this study was to examine the differences in glucose and insulin responses between African-American and Caucasian youths and to determine the associations of between-group differences with sex, body mass index (BMI) and pubertal status using a noncompartmental pharmacokinetic approach. Sixteen African-American and 22 Caucasian healthy adolescents were tested using the frequently sampled intravenous glucose tolerance test. Longitudinal t-tests across each observation revealed that (1) African-American youths have higher insulin concentrations between 4 to 19 min; (2) insulin levels remained similar as subjects were grouped according to sex and pubertal status; (3) for glucose, the only difference was found as it approached steady-state basal level (>100 min) between groups ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2269824 Tue, 17 Mar 2009 04:00:00 +0100 2269824 http://www.medworm.com/index.php?rid=2264124&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.651 It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2264124 Sat, 14 Mar 2009 04:00:00 +0100 2264124 http://www.medworm.com/index.php?rid=2231524&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.649 This study showed that pharmacokinetics factors of morphine and M6G in children were significantly different from adults. Therefore the required dose for children should be different from that of adults and should be based on studies performed on children rather than on studies on adults. Some adverse effects, particularly nausea and pruritus, may be commoner than is usually thought, while others, particularly respiratory problems did not occur. Copyright © 2009 John Wiley & Sons, Ltd. (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2231524 Wed, 04 Mar 2009 05:00:00 +0100 2231524 http://www.medworm.com/index.php?rid=2226631&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.650 The purpose of this study was to investigate the correlation between mRNA and protein levels for P-glycoprotein (P-gp) expressed in various cell lines to validate the estimation of P-gp activity from its mRNA levels. P-gp expression levels in various cell monolayers, normal, P-gp-induced, P-gp-highly induced, (multidrug resistance, MDR) MDR1-knockdown (A2-2) and MDR1-knockdown (B2-2) Caco-2 cells and MDCKII/MDR1 cells, were quantified by real-time quantitative polymerase chain reaction (PCR) and western blot analysis. Both mRNA and protein levels of P-gp were lowest in the MDR1-knockdown (B2-2) Caco-2 cells, followed by the MDR1-knockdown (A2-2) Caco-2, normal Caco-2, P-gp-induced Caco-2 and P-gp-highly induced Caco-2 cells, and highest in the MDCKII/MDR1 cells. Except for the MDCKII/MDR1 ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2226631 Mon, 02 Mar 2009 05:00:00 +0100 2226631 http://www.medworm.com/index.php?rid=2199558&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.645 A novel 5-aminolevulinic acid (ALA)-containing microparticulate system was produced recently, based on incorporation of ALA into particles prepared from a suppository base that maintains drug stability during storage and melts at skin temperature to release its drug payload. The novel particulate system was applied to the skin of living animals, followed by study of protoporphyrin IX (PpIX) production. The effect of formulating the microparticles in different vehicles was investigated and also the phototoxicity of the PpIX produced using a model tumour.Particles formulated in propylene glycol gels (10% w/w ALA loading) generated the highest peak PpIX fluorescence levels in normal mouse skin. Peak PpIX levels induced in skin overlying subcutaneously implanted WiDr tumours were significantly... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2199558 Fri, 20 Feb 2009 17:12:13 +0100 2199558 http://www.medworm.com/index.php?rid=2199562&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.646 The aim of this study was to investigate the effect of anesthesia on the pharmacokinetics of bromosulfophthalein (BSP) with focus on biliary clearance. The plasma concentration profile and biliary clearance of intravenously administered BSP was compared in conscious freely moving bile duct catheterized rats and rats anesthetized with ketamine or Zoletil. The plasma concentration of BSP in conscious rats was similar to that of anesthetized rats, irrespective of the anesthetic used. There was no significant difference in the volume of distribution, total body clearance and mean residence time of BSP between the groups. The biliary clearance of BSP in rats anesthetized using ketamine or Zoletil was also similar to that of conscious rats. Only bile flow was increased under anesthetization comp... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2199562 Thu, 19 Feb 2009 05:00:00 +0100 2199562 http://www.medworm.com/index.php?rid=2199561&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.644 In this study, 9 mg/kg verapamil was administered orally to Sprague-Dawley rats 30 min after the oral administration of 2 and 10 mg/kg of oral EGCG. Compared with the controls, the AUC values of both verapamil (74.3% and 111% increase for 2 and 10 mg/kg EGCG, respectively) and norverapamil (51.5% and 87.2% increase for 2 and 10 mg/kg EGCG, respectively) were significantly greater in the presence of EGCG. However, compared with the controls, both the AUC and the relative bioavailability of verapamil were significantly (p (Source: Biopharmaceutics and Drug Disposition) Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2199561 Thu, 19 Feb 2009 05:00:00 +0100 2199561 http://www.medworm.com/index.php?rid=2199560&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.648 The pharmacokinetics of pyrrole (Py)-imidazole (Im) polyamides was studied in rats after the intravenous administration of these compounds. Py-Im polyamide (A) was composed of Ac-ImPyPy-ImPyPy-[beta]-Dp ([beta]: [beta]-alanine, Dp: N,N-dimethylaminopropylamide). Py-Im polyamide (B) was composed of Ac-PyIm-[beta]-ImIm-PyPy-[beta]-PyPy-[beta]-Dp. Py-Im polyamide (C) was composed of Ac-PyPy-[beta]-PyImPy-PyPyPy-[beta]-ImPy-[beta]-Dp. The molecular weight of Py-Im polyamide (A) was 1035.12, that of Py-Im polyamide (B) was 1422.51 and that of Py-Im polyamide (C) was 1665.78. After the intravenous injection of Py-Im polyamide (A) at 1.3, 2.0, 7.5 and 15.0 mg/kg, Py-Im polyamides (B) and (C) at 1.0, 2.0, 3.0 and 5.0 mg/kg, the average systemic clearance and the volume of distribution at the stead... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2199560 Thu, 19 Feb 2009 05:00:00 +0100 2199560 http://www.medworm.com/index.php?rid=2199559&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.647 In this study, the role of biopharmaceutical factors that contribute to negative food effects was studied using furosemide, nadolol, tacrine and atenolol (as model compounds exhibiting negative food effects), and prednisolone, hydrochlorothiazide and ibuprofen (as model compounds that do not show any food effects). The physiological pH of the upper intestinal tract is lower, at pH 5, in the postprandial state when compared with the preprandial state, pH 6.5. Drugs that exhibited negative food effects had low apical to basolateral Caco-2 permeabilities, low pKa/pKb and Log P values of less than 1. The drugs exhibiting negative food effects had low distribution coefficients at the pH conditions of the fed and fasted states. Furosemide, being a hydrophilic, poorly soluble acidic drug showed l... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2199559 Thu, 19 Feb 2009 05:00:00 +0100 2199559 http://www.medworm.com/index.php?rid=2120637&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.643 Mechanisms related to the adverse effects of corticosteroids on glucose homeostasis were studied. Five groups of adrenalectomized (ADX) rats were given methylprednisolone (MPL) intravenously at 10 and 50 mg/kg, or a continuous 7 day infusion at rates of 0, 0.1, 0.3 mg/kg/h via subcutaneously implanted Alzet mini-pumps. Plasma concentrations of MPL, glucose and insulin were determined at various time points up to 72 h after injection or 336 h after infusion. The pharmacokinetics of MPL was captured with a two-compartment model. The Adapt II software was used in modeling. Injection of MPL caused a temporary glucose increase over 6 h by stimulating gluconeogenesis. The glucose changes stimulated pancreatic [beta]-cell secretion yielding a later insulin peak at around 10 h. In turn, insulin ca... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2120637 Thu, 22 Jan 2009 05:00:00 +0100 2120637 http://www.medworm.com/index.php?rid=2120638&cid=s_33588_13_f&fid=33588&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fbdd.642 A physiologic pharmacodynamic model was developed to jointly describe the effects of methylprednisolone (MPL) on adrenal suppression and glycemic control in normal rats. Six groups of animals were given MPL intravenously at 0, 10 and 50 mg/kg, or by subcutaneous 7 day infusion at rates of 0, 0.1 and 0.3 mg/kg/h. Plasma concentrations of MPL, corticosterone (CST), glucose and insulin were determined at various times up to 72 h after injection and 336 h after infusion. The pharmacokinetics of MPL was described by a two-compartment model. A circadian rhythm for CST was found in untreated rats with a stress-altered baseline caused by handling, which was captured by a circadian harmonic secretion rate with an increasing mesor. All drug treatments caused CST suppression. Injection of MPL caused ... Biopharmaceutics and Drug Disposition journals http://www.medworm.com/rss/comments.php?id=2120638 Tue, 20 Jan 2009 05:00:00 +0100 2120638