Biopharmaceutics & Drug Disposition (Biopharm Drug Dispos)

Publisher: Wiley

Journal description

The Journal publishes original reports of studies in biopharmaceutics drug disposition and pharmacokinetics especially those which have a direct relation to the therapeutic use of drugs. This includes human pharmacological studies and therapeutic response and toxicity related to plasma and tissue concentrations of drugs and their metabolites. Research on factors affecting the disposition of the clinical response to drugs and on the design of drug dosage regimens and the treatment of overdose based on pharmacokinetic principles are accepted. Papers on analytical methodology in vitro drug metabolism and on animal models are also published provided that either they facilitate the preceding types of investigation or they are related to the use of drugs in man. The Journal also publishes review articles.

Current impact factor: 2.34

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 2.34
2013 Impact Factor 2.178
2012 Impact Factor 2.09
2011 Impact Factor 2.074
2010 Impact Factor 1.394
2009 Impact Factor 1.246
2008 Impact Factor 1.542
2007 Impact Factor 1.238
2006 Impact Factor 1.152
2005 Impact Factor 1.11
2004 Impact Factor 1.068
2003 Impact Factor 1.763
2002 Impact Factor 0.688
2001 Impact Factor 0.772
2000 Impact Factor 0.819
1999 Impact Factor 1.068
1998 Impact Factor 0.789
1997 Impact Factor 0.802
1996 Impact Factor 0.824
1995 Impact Factor 0.737
1994 Impact Factor 0.809
1993 Impact Factor 0.609
1992 Impact Factor 0.595

Impact factor over time

Impact factor

Additional details

5-year impact 2.20
Cited half-life 7.90
Immediacy index 0.40
Eigenfactor 0.00
Article influence 0.54
Website Biopharmaceutics & Drug Disposition website
Other titles Biopharmaceutics & drug disposition (Online), Biopharmaceutics & drug disposition, Biopharmaceutics and drug disposition
ISSN 1099-081X
OCLC 43974207
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details


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    • 12 months embargo
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    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
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    • Non-Commercial
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    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated whether quinolone antibiotics inhibit PEPT1-mediated uptake of its substrates. Among the quinolones examined, lomefloxacin, moxifloxacin (MFLX) and purlifloxacin significantly inhibited uptake of PEPT1 substrate phenylalanine-Ψ(CN-S)-alanine (Phe-Ψ-Ala) in HeLa/PEPT1 cells to 31.6 ± 1.3%, 27.6 ± 2.9%, 36.8 ± 2.2%, and 32.6 ± 1.4%, respectively. Further examination showed that MFLX was an uncompetitive inhibitor, with an IC50 value of 4.29 ± 1.29 mM. In addition, MFLX significantly decreased cephalexin and valacyclovir uptake in HeLa/PEPT1 cells. In an in vivo study in rats, the maximum plasma concentration (Cmax) of orally administered Phe-Ψ-Ala was significantly decreased in the presence of MFLX (171 ± 1 ng/mL) compared with that in its absence (244 ± 9 ng/mL). The area under the concentration-time curve (AUC) of orally administered Phe-Ψ-Ala in the presence of MFLX (338 ± 50 ng/mL・hr) tended to decrease compared with that in its absence (399 ± 75 ng/mL・hr). The oral bioavailability of Phe-Ψ-Ala in the presence and absence of MFLX was 41.7 ± 6.2% and 49.2 ± 9.2%, respectively. Our results indicate that administration of quinolone antibiotics concomitantly with PEPT1 substrate drugs may potentially result in drug-drug interaction. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2015; DOI:10.1002/bdd.1999
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    ABSTRACT: Purpose: The two-compartment linear model that used to describe the population pharmacokinetics (PK) of many therapeutic monoclonal antibodies (TMAbs) offered little biological insight of antibody disposition in human. The purpose of this study is to develop a semi-mechanistic FcRn-mediated IgG disposition model to describe the population PK of TMAbs in clinical patients. Methods: A standard two-compartment linear PK model from a previously published population PK model of pertuzumab was used to simulate intensive PK data of 100 subjects for model development. Two different semi-mechanistic FcRn-mediated IgG disposition models were developed and FOCE with interaction method in NONMEM was used to obtain the final model estimates. The performances of these models were then compared to the two-compartment linear PK model that used to simulate the data for model development. Results: A semi-mechanistic FcRn-mediated IgG disposition model which consisted of peripheral tissue compartment and FcRn-containing endosomes in the central compartment best describe the simulate pertuzumab population PK data. This developed semi-mechanistic population PK model had the same number of model parameters, produced very similar concentration-time profiles but provided additional biological insight about the FcRn-mediated IgG disposition in human subjects compared to the standard linear two-compartment linear PK model. Conclusion: This first reported semi-mechanistic model may serve as important model framework for developing future population PK model of TMAbs in clinical patients. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2015; DOI:10.1002/bdd.1997
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    ABSTRACT: Cynomolgus monkeys are widely used in drug developmental stages as non-human primate models. Previous studies used 89 compounds to investigate species differences associated with cytochrome P450 (P450 or CYP) function that reported monkey specific CYP2C76 cleared 19 chemicals, and homologous CYP2C9 and CYP2C19 metabolized 17 and 30 human CYP2C9 and/or CYP2C19 substrates, respectively. In the present study, 22 compounds selected from viewpoints of global drug interaction guidances and guidelines were further evaluated to seek potential substrates for monkey CYP2C8, which is highly homologous to human CYP2C8 (92%). Amodiaquine, montelukast, quercetin, and rosiglitazone, known as substrates or competitive inhibitors of human CYP2C8, were metabolically depleted by recombinant monkey CYP2C8 at relatively high rates. Taken together with our reported findings of slow eliminations of amodiaquine and montelukast by monkey CYP2C9, CYP2C19, and CYP2C76, the present results suggest that these at least four chemicals may be good marker substrates for monkey CYP2C8. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2015; DOI:10.1002/bdd.1998
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    ABSTRACT: Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood:plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2015; DOI:10.1002/bdd.1996
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    ABSTRACT: Objective: The aim of this research work is to characterize metabolism of S002-333, (2-(4'-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide) and its enantiomers, S004-1032 (R-form) and S007-1558 (S-form) in pooled human liver microsomes (PHLM) and pooled liver microsomes (LM) of rat (RLM), rabbit (RABLM), dog (DLM), monkey (MLM). Another objective of this study is to identify suitable surrogate species to humans for further development of lead candidates. Method: In-vitro metabolic stability and metabolite identification of S002-333 and enantiomers were carried out in PHLM and LM of various species. Prediction of surrogate species and in-vitro in-vivo extrapolation were performed based upon calculated in-vitro intrinsic clearance (CLint ). Results/conclusion: In-vitro CLint values for S002-333, S004-1032 and S007-1558 were 0.027 ± 0.005, 0.025 ± 0.004 and 0.036 ± 0.005 mL/min/mg respectively in PHLM, indicating S007-1558, the most metabolically unstable among the three. LM of other species showed similar results. Common surrogate species to humans for S002-333 and enantiomers was predicted as rabbit where extrapolated hepatic clearance (CLH ) did not show significant difference with in-vivo CLH values. However, none of the species closely mimic to humans with respect to proportion of major metabolites (M-1 through M-4) formed in-vitro. Likewise, CLH values were also predicted in humans for S002-333 and enantiomers using various mathematical models. During analysis, there was no chiral inversion evident among individual isomers throughout in-vitro and in-vivo experiments. In conclusion, in-vitro results indicate prominent role of phase-I metabolism in degradation of S002-333 and enantiomers and predict rabbit as an alternative species to conduct further safety and efficacy studies. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 10/2015; DOI:10.1002/bdd.1995
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    ABSTRACT: Mechanisms of absorption, distribution, metabolism and elimination of small and large molecule therapeutics differ significantly from one another and can be explored within the framework of a physiologically-based pharmacokinetic (PBPK) model. We briefly review fundamental approaches to PBPK modeling, in which drug kinetics within tissues and organs are explicitly represented using physiologically meaningful parameters. Differences in PBPK models applied to small/large molecule drugs are highlighted, thus elucidating differences in absorption, distribution and elimination properties between these two classes of drugs in a systematic manner. Absorption of small and large molecules differs with respect to their common extravascular routes of delivery (oral versus subcutaneous). The role of the lymphatic system in drug distribution, and involvement of tissues as sites of elimination (through catabolism and target mediated drug disposition) are unique features of antibody distribution and elimination that differ from small molecules, which are commonly distributed into the tissues but are eliminated primarily by liver metabolism. Fundamental differences exist in the ability to predict human pharmacokinetics based upon preclinical data due to differing mechanisms governing small and large molecule disposition. These differences have influence on the evolving utilization of PBPK modeling in discovery and development of small and large molecule therapeutics. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 10/2015; DOI:10.1002/bdd.1994
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    ABSTRACT: Zidovudine (AZT) is one of the most frequently used antiretroviral drugs in prevention of perinatal transmission of HIV. However, safety concerns on AZT use in pregnancy still persist as severe side effects are associated with AZT exposure in children. In our study we aimed to contribute to current knowledge on AZT transplacental transport and to evaluate potential involvement of the main human drug efflux ATP-binding cassette (ABC) transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and multidrug resistance-associated proteins 2 and 5 (ABCC2 and ABCC5) in the disposition of AZT between mother and fetus. In order to elucidate this issue we investigated the effect of selected ABC transporters on AZT transepithelial transport across MDCKII cell monolayers. In addition we used the in situ method of dually perfused rat term placenta to further study the role of ABC transporters in AZT transplacental transport. In vitro studies revealed significant effect of ABCB1 and ABCG2 on AZT transport which was subsequently confirmed also on organ level. Lamivudine, an antiretroviral agent commonly co-administered with AZT, did not affect ABC transporter-mediated AZT transfer. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2015; DOI:10.1002/bdd.1993
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    ABSTRACT: Chimeric mice with humanized livers (PXB mice) are used to investigate the metabolism and pharmacokinetics of drugs in humans. However, residual murine enzymatic activities derived from the liver and presence of mouse small intestinal metabolism can hamper the prediction of human drug metabolism. We recently developed murine Cytochrome P450 3a gene knockout chimeric mice with humanized livers (Cyp3a KO CM). To evaluate the prediction of drug metabolism, nefazodone (NEF) was orally administered at 10 mg/kg to the following mice strains: Cyp3a KO CM, murine Cyp3a gene knockout (Cyp3a KO), PXB, and severe combined immunodeficiency (SCID) mice. Liquid chromatography-mass spectrometry was used for metabolic profiling of plasma, urine, and bile. Prediction of human metabolite levels such as hydroxy nefazodone (OH-NEF), triazoledione form (TD), m-chlorophenylpiperazine, and dealkyl metabolites in Cyp3a KO CM was superior to that in Cyp3a KO, PXB, or SCID mice. Further, clinical exposure levels of NEF, OH-NEF, and TD were reproduced in Cyp3a KO CM. In contrast, NEF was rapidly metabolized to TD in both PXB and SCID mice but not in Cyp3a KO mice, suggesting that murine CYP3A is involved in the elimination of NEF in these mice. These findings demonstrate that the metabolic profile of NEF in Cyp3a KO CM qualitatively and quantitatively differs from that in PXB mice due to the higher metabolic rate of NEF and its metabolites via murine CYP3A. Cyp3a KO CM might therefore be useful in predicting the metabolic profiles of drug candidates in humans. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2015; DOI:10.1002/bdd.1990
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    ABSTRACT: Cynomolgus monkeys are widely used in preclinical studies as non-human primate species. The amino acid sequence of cynomolgus monkey cytochrome P450 (P450 or CYP) 2C19 is reportedly highly correlated to that of human CYP2C19 (92%) and CYP2C9 (93%). In the present study, eighty nine commercially available compounds were screened to find potential substrates for cynomolgus monkey CYP2C19. Of 89 drugs, 34 were metabolically depleted by cynomolgus monkey CYP2C19 with relatively high rates. Among them, 30 compounds have been reported as substrates or inhibitors of, either or both, human CYP2C19 and CYP2C9. Several compounds, including loratadine, showed high selectivity to cynomolgus monkey CYP2C19, and all of these have been reported as human CYP2C19 and/or CYP2C9 substrates. In addition, cynomolgus monkey CYP2C19 formed the same loratadine metabolite as human CYP2C19, descarboethoxyloratadine. These results suggest that cynomolgus monkey CYP2C19 is generally similar to human CYP2C19 and CYP2C9 in its substrate recognition functionality. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2015; DOI:10.1002/bdd.1991
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    ABSTRACT: CYP2A6 is a major hepatic member of the cytochrome P450 family in humans. Much variation in CYP2A6 levels and activity can be attributed to genetic polymorphisms of this gene. CYP2A6*25 comprises an amino acid substitution, F118L. To clarify the effect of the leucine substitution at position 118 in CYP2A6.25, this variant, wild type CYP2A6 and three additional variants consisting of artificial mutations at the substrate binding site (position 481) suggested by earlier reports using random mutagenesis studies [CYP2A6.1, CYP2A6.25, CYP2A6.1(F118A), CYP2A6.1(A481G) and CYP2A6.25(A481G)], were co-expressed with NADPH-cytochrome P450 reductase in E. coli. The hydroxylase activity of these variants toward 7-ethoxycoumarin, coumarin, flavone, α-naphthoflavone, flavanone and hydroxyflavanone were examined. All the mutants had lower activities for coumarin 7-hydroxylation than the wild type. All the mutants showed higher activities for flavone and α-naphthoflavone compared with CYP2A6.1. CYP2A6.1 had the highest flavanone 2'-hydroxylase activity, whereas CYP2A6.25 had the highest 6- and 4'-hydroxylase activities. CYP2A6.1(F118A), CYP2A6.1(A481G) and CYP2A6.25(A481G) had higher flavanone 3'-hydroxylase activities than CYP2A6.1 and CYP2A6.25. Furthermore, 4'-hydroxyflavanone was metabolized by CYP2A6.25. These results indicate that the CYP2A6.25 mutation confers new substrate specificity towards flavonoids. Copyright © 2015 John Wiley & Sons, Ltd.
    Biopharmaceutics & Drug Disposition 09/2015; DOI:10.1002/bdd.1966
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    ABSTRACT: Domperidone is a dopamine receptor antagonist and a substrate of CYP3A4, hence a potential for CYP3A inhibition-based drug-drug interactions (DDI). A physiologically-based pharmacokinetic model was developed to describe DDIs between domperidone and three different inhibitors of CYP3A4. Simcyp V13.1 was used to simulate human domperidone pharmacokinetics and DDIs. Inputs included domperidone chemical and physical properties (LogP, pKa, etc.), in-vitro human liver microsomal data, and pharmacokinetic parameters from single-dose intravenous clinical studies in healthy participants. Simulated mean maximum domperidone plasma concentration and AUC after single- and multiple-oral doses under diverse conditions were within 1.1-1.4 fold of observed values. Simulated intestinal availability, hepatic availability, and fraction absorbed were 0.45 ± 0.14, 0.31 ± 0.10 and 0.89 ± 0.11, respectively, and comparable to observed in vivo values. Simulated ratios of AUC and Cmax in presence of ketoconazole, erythromycin or itraconazole to baseline were consistent with observed ratios. Simulated ketoconazole, erythromycin, itraconazole and Cmax,ss and AUCss were within 1.5-fold of observed values. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 09/2015; DOI:10.1002/bdd.1992
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    ABSTRACT: Flavonoids occur naturally as glucosides and aglycones. Their common phenolic hydroxyl groups may trigger extensive UDP-glucuronosyltransferase (UGT)- catalyzed metabolism. Unlike aglycones, glucosides contain glucose moieties. However, the influence of these glucose moieties on glucuronidation of glucosides and aglycones remains unclear. In this study, the flavonoid glucoside tilianin and its aglycone acacetin were used as model compounds. The glucuronidation characteristics and enzyme kinetics of tilianin and acacetin were compared using human UGT isoforms, liver microsomes, and intestinal microsomes obtained from different animal species. Tilianin and acacetin were metabolized into different glucuronides, with UGT1A8 produced as the main isoform. Assessment of enzyme kinetics in UGT1A8, human liver microsomes, and human intestinal microsomes revealed that compared with tilianin, acacetin displayed lower Km (0.6-, 0.7-, and 0.6-fold, respectively), higher Vmax (20-, 60-, and 230-fold, respectively) and higher clearance (30-, 80-, and 300-fold, respectively). Furthermore, glucuronidation of acacetin and tilianin showed significant species- and gender-dependent differences. In conclusion, glucuronidation of flavonoid aglycones is faster than that of glucosides in the intestine and the liver. Understanding the metabolism and species- and gender-dependent differences between glucosides and aglycones is crucial for development of drugs from flavonoids. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1989
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    ABSTRACT: We evaluated if the renal function decline rates per year with age in adults vary based on two primary statistical analyses: cross-section (CS), using one observation per subject, and, longitudinal (LT), using multiple observations per subject along a time. A total of 16,628 records (3,946 subjects; age ranged from 30 to 92 years) of creatinine clearance and relevant demographic data were used. On an average, 4 samples per subjects were collected up to 2,364 days (mean: 793 days). A simple linear regression and random coefficient models were selected for CS and LT analyses, respectively. The renal function decline rates per year were 1.33 and 0.95 mL/min/year for CS and LT analyses, respectively, and, are slower when the repeated individual measurements are considered. Our study confirms that rates are different based on statistical analyses, and, that a statistically robust longitudinal model with a proper sampling design provides reliable individual as well as population estimates of the renal function decline rates per year with age in adults. In conclusion, our findings indicated that one should be cautious in interpreting the renal function decline rate with aging information because its estimation was highly depended on the statistical analyses. From our analyses, a population LT analysis (e.g., random coefficient model) is recommended if individualization is critical, such as a dose adjustment based on the renal function during a chronic therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1988
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    ABSTRACT: Entacapone is an inhibitor of catechol-O-methyltransferase (COMT) and is being used to extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. Entacapone has low and variable oral bioavailability and the underlying mechanism(s) for this behavior have not been studied. To explain such behavior and to characterize the dynamic changes in metabolism of entacapone, we developed a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model integrating in silico, in vitro, and in vivo pharmacokinetic data. The model was developed and verified in healthy volunteers and subsequently expanded to predict the pharmacokinetic parameters of entacapone phosphate, a prodrug of entacapone, and to assess the impact of hepatic impairment on pharmacokinetics of entacapone. Low and inter-individual variability in bioavailability could be attributed to the extensive first-pass metabolism by UGTs in the liver and, to a lesser extent, small intestine. The predictive performance of this model was acceptable with predicted Cmax , AUC, and PD parameters lie within 20% of the observed data. The model indicates that the low bioavailability could be attributed to the extensive first-pass effect of entacapone. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1986
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    ABSTRACT: PurposeRepaglinide and pioglitazone are both CYP2C8 and CYP3A4 substrates. This study is to determine whether repaglinide has an inhibitory effect on the metabolism of pioglitazone in vitro,in silico and in vivo.Method In vitro, the effect of repaglinide on the metabolism of pioglitazone was assessed in pooled human liver microsomes. In silico, an IVIVE-PBPK linked model was built with Simcyp®. Then, a randomized, 2-phase cross-over clinical study was conducted in 12 healthy volunteers.ResultsRepaglinide showed a strong inhibitory effect on the metabolism of pioglitazone in vitro (Ki = 0.0757 μM), [I]/Ki > 0.1. The Simcyp® prediction ratios of AUC and Cmax between the two treatment groups were both about 1.01. The pharmacokinetics of poglitazone in clinical trials showed no significant difference between these two treatment groups (P > 0.05).Conclusion Repaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo,which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 08/2015; DOI:10.1002/bdd.1987
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    ABSTRACT: There is an ongoing debate on the use of single concentration time point C2 for therapeutic drug monitoring (TDM) and exposure prediction for cyclosporine. The objective of the present work was to evaluate the relationship between peak concentration (Cmax ) versus area under the curve (AUC) for cyclosporine. Using published data from renal transplant patients from a 8-12 week study with two formulations, a simple linear regression model represented by AUC - cyclosporine = Cmax - Cyclosporine × 3.9965 + 384.5 (r = 0.9647; p < 0.001) was developed. Using the regression equation, predictions of AUC from the reported Cmax data were performed; the fold difference between observed vs predicted AUC was computed and root mean square error for the prediction was calculated. While all but one of the predicted AUCs were contained within 0.5-to 2-fold difference (99.1%), a greater proportion of the AUC values were predicted within a narrower range of 0.75 to 1.5-fold difference (78.2%) suggesting the utility of Cmax as the right surrogate for predicting AUC for cyclosporine with a correlation coefficient of 0.8698 (n = 126; P < 0.001) and RMSE of 26.2%. Since time to Cmax generally varies from 1 to 2 hours, although the results validate the use of C2, there may be an opportunity to explore the suitability of C1 or C1.5 in a prospective study for the purpose of TDM and AUC prediction of cyclosporine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 07/2015; DOI:10.1002/bdd.1967
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    ABSTRACT: The in vitro metabolism of (-)-cis- and (-)-trans-rose oixde was investigated using human liver microsomes and recombinant cytochrome P450 (P450 or CYP) enzymes for the first time. Both isomers of rose oxide were incubated with human liver microsomes, and the formation of respective 9-oxidized metabolite was determined by using gas chromatography-mass spectrometry (GC-MS). Of 11 different recombinant human P450 enzymes used, CYP2B6 and CYP2C19 were the primary enzymes catalyzing the metabolism of (-)-cis- and (-)-trans-rose oxide. CYP1A2 also efficiently oxidized (-)-cis-rose oxide at the 9-position but did not (-)-trans-rose oxide. α-Naphthoflavone (a selective CYP1A2 inhibitor), thioTEPA (a CYP2B6 inhibitor) and anti-CYP2B6 antibody inhibited (-)-cis-rose oxide 9-hydroxylation catalyzed by human liver microsomes. On the other hand, the metabolism of (-)-trans-rose oxide was suppressed by thioTEPA and anti-CYP2B6 at significant level in human liver microsomes. However, omeprazole (a CYP2C19 inhibitor) had no significant effects on the metabolism of both isomers of rose oxide. Using microsomal preparations from 9 different human liver samples, (-)-9-hydroxy-cis- and (-)-9-hydroxy-trans-rose oxide formations correlated with (S)-mephenytoin N-demethylase activity (CYP2B6 marker activity). These results suggest that CYP2B6 plays important roles on the metabolism of (-)-cis- and (-)-trans-rose oxide in human liver microsomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1965
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    ABSTRACT: Mefenamic acid (MEF) is a widely prescribed non-steroidal anti-inflammatory drug that has been found associated with rare but severe cases of hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. Formation of protein-reactive acylating metabolites such as 1-O-acyl-MEF glucuronide (MEFG) and 3'-hydroxymethyl-MEF 1-O-acyl-glucuronide is one proposed cause. In addition to the well-reported 3'-hydroxymethyl-MEF, two mono-hydroxyl-MEF (OH-MEFs) were recently identified in vitro. However, in vivo evidence and whether these OH-MEFs would be further glucuronidated to the potentially reactive 1-O-acyl-glucuronides (OH-MEFGs) is lacking. Utilizing UPLC-Q-TOF/MS and LC-MS/MS, the current study for the first time identified four OH-MEFs and their corresponding OH-MEFGs from plasma after single oral MEF (40 mg/kg) administration to rats, including an OH-MEF that has not been previously reported. The systemic exposure of these identified metabolites was high, with metabolic to parent AUC0→24h ratios reaching 23-52% (OH-MEFs) and 8-29% (OH-MEFGs). These metabolites also had long systemic exposure time in both single and 5-day multiple oral MEF-treated rats, with elimination half-lives between 9 h and >24 h. In addition to these novel metabolites, the previously reported MEFG was also identified and its systemic exposure was found to be doubled after multiple MEF administrations. These pharmacokinetic results suggest that systemic toxicities caused by the potentially reactive MEFG and OH-MEFGs could be considerable, especially after repeated MEF treatment. Nevertheless, MEFG and OH-MEFGs had negligible brain uptakes, indicating minimal risk of brain toxicities. Furthermore, in situ intestinal perfusion study revealed that during MEF absorption, it was extensively metabolized to MEFG while <5% was metabolized to OH-MEFs and OH-MEFGs. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1964
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    ABSTRACT: Protein phosphorylation is a vital posttranslational modification. In this study, we investigated the effect of phosphorylation on human uridine diphosphate (UDP)-glucuronosyltransferase 1A3 (UGT1A3) activity. Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so we examined three predicted PKC phosphorylationsites inUGT1A3. Site-directed mutation analysis at residues 28, 43, and 436 (from serine to glycine) was conducted. Compared with the wild-type, the S43G-mutant showed significantly decreased UGT1A3 catalytic activity. Furthermore, the UGT1A3 activity of wild-type and S43G-mutant was downregulated by calphostin C, whereas the calphostin C inhibitory effect was much weaker on S43G-mutant than wild-type. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1963
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    ABSTRACT: 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ-opioid receptor. AZD2327 and N-deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time-dependent inhibition of CYP3A4. The aim of current work was to develop a physiologically based pharmacokinetic (PBPK) model to quantitatively predict the magnitude of CYP3A4 mediated drug-drug interaction with midazolam as the substrate. Integrating in silico, in vitro, and in vivo PK data, a PBPK model was successfully developed to simulate clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (Cmax ) and area under the concentration-time curve (AUC) for midazolam were increased by 1.75 and 2.45-fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinical relevant drug-drug interactions (DDI). These results are in agreement with those obtained in a clinical trial of 1.4 and 1.5-fold increase in Cmax and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than two-fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways, and inhibitors (parent and metabolite) can be predicted using well developed PBPK model. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 06/2015; DOI:10.1002/bdd.1962