Biopharmaceutics & Drug Disposition (Biopharm Drug Dispos )

Publisher: John Wiley & Sons

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.

  • Impact factor
    2.09
  • 5-year impact
    1.73
  • Cited half-life
    8.10
  • Immediacy index
    0.57
  • Eigenfactor
    0.00
  • Article influence
    0.46
  • 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

John Wiley & Sons

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    • Author can archive a pre-print version
  • Post-print
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    • See Wiley-Blackwell entry for articles after February 2007
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    • Articles in some journals can be made Open Access on payment of additional charge
    • 'John Wiley and Sons' is an imprint of 'Wiley-Blackwell'
  • Classification
    ​ green

Publications in this journal

  • [show abstract] [hide abstract]
    ABSTRACT: Pharmacokinetic studies concerning D-penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose D-penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on D-penicillamine disposition in order to guide future clinical studies on the anti-relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on D-penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of D-penicillamine were performed using young or adult ethanol-naïve rats or adult ethanol-experienced (subjected to a long-term ethanol self-administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalizedAUC0∞, V1 and k10 revealed that disposition, in the range plasma concentrations assayed, is non-linear both in young ethanol-naïve and in adult ethanol-experienced rats. Notably, no significant changes in t1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t1/2 . D-penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non-linear, the lack of significant alterations of the t1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters DP disposition but, again, does not modify t1/2 . This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2014;
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    ABSTRACT: The microsomal protein per gram of liver (MPPGL) is an important scaling factor in the in vitro-in vivo extrapolation of metabolic data obtained in liver microsomes. This study aimed to determine the MPPGL in 4 biliary atresia patients (0.6 - 1.6 years old) undergoing liver transplantation, as it is known that the MPPGL is affected by age and possibly by liver disease. Due to presence of bilirubin in the homogenates and microsomes, the NADPH-cytochrome reductase activity was used to determine the recovery factor, rather than methods using the dithionite difference spectrum. A mean value of 18.73 (±2.82) mg/g (geometric mean ± SD, n = 4) was observed, which is lower than the expected MPPGL based on the age of the patients (26.60 ± 0.40 mg/g). This suggests a decreased amount of microsomal protein in the livers of biliary atresia patients. Moreover, no differences in MPPGL between different zones of the liver could be detected. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2014;
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    ABSTRACT: YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for treatment of drug addiction. However, the earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism, and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then simulate the clinical PK of YQA-14 using physiologically-based pharmacokinetics (PBPK) model to assess the likelihood of development of YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species rats and dogs for a validation purpose. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have clearance of 8.0 mL/min/kg, a volume distribution of 1.7 L/kg, and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 as an improved candidate for further research and develop as a potential DA D3R antagonism for treatment of drug addiction in clinic. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 03/2014;
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    ABSTRACT: The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, we established an in vitro system to evaluate β-glucuronidase-mediated deconjugation and examined the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-d-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50 ) value of 30.4 μM. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 02/2014;
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    ABSTRACT: Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4-hydroxy tolbutamide (4-OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407-induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration-time curve (AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non-renal clearance (CLNR ). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4-hydroxylated metabolite formation ratio (AUC4-OHTB /AUCTB ) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CLint (by 28.8%) for metabolism of tolbutamide to 4-OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CLint changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state. Copyright © 2014 John Wiley & Sons, Ltd.
    Biopharmaceutics & Drug Disposition 02/2014;
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    ABSTRACT: Choline is essential for the synthesis of the major membrane phospholipid phosphatidylcholine (PC), the methyl donor betaine, and the neurotransmitter acetylcholine (ACh). Elevated levels of choline and up-regulated choline kinase activity have been detected in various cancers. Thus, the intracellular accumulation of choline through choline transporters is the rate-limiting step in phospholipid metabolism and a prerequisite for cancer cell proliferation. Previous studies have demonstrated abnormalities in choline uptake and choline phospholipid metabolism in cancer cells using the imaging of cancer with positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). The aberrant choline metabolism in cancer cells is strongly correlated with their malignant progression. Using quantitative real-time PCR, we measured the mRNA expression of choline transporters, and found that choline transporter-like proteins CTLs/SLC44 family are highly expressed in various cancer cell lines. Choline uptake through CTLs is associated with cell viability, and the functional inhibition of CTLs could promote apoptotic cell death. Furthermore, non-neuronal cholinergic systems that include CTLs-mediated choline transport are associated with cell proliferation and their inhibition promotes apoptotic cell death in colon cancer, small cell lung cancer and human leukemic T-cells. The identification of this new CTLs-mediated choline transport system provides a potential new target for cancer therapy. Copyright © 2014 John Wiley & Sons, Ltd.
    Biopharmaceutics & Drug Disposition 02/2014;
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    ABSTRACT: We have reported an unusual, but clinically significant, digoxin (DIG)-bupropion (BUP) drug interaction (DDI), where BUP increased DIG renal clearance by 80%. To investigate the mechanism(s) of this unusual DDI, we first determined the effect of BUP, its circulating metabolites or their combination on [(3) H]-DIG transport by cells expressing human P-gp or human OATP4C1. Second, we asked whether this DDI could be replicated in the rat so that it could be used to conduct mechanistic studies. Then, we tested the effect of BUP and its rat metabolites on [(3) H]-DIG transport by cells expressing rat Oatp4c1. BUP and its metabolites had no effect on human P-gp mediated transepithelial transport of [(3) H]-DIG. BUP and hydroxybupropion (HBUP) significantly stimulated H-OATP4C1 mediated transport of [(3) H]-DIG. And BUP cocktail (BUP plus its metabolites) significantly increased H-OATP4C1 mediated transport of [(3) H]-DIG, and partially reversed the inhibition by 100 μM DIG. However, erythro-hydrobupropion (EBUP) and threo-hydrobupropion (TBUP) did not affect [(3) H]-DIG uptake by H-OATP4C1 cells. BUP administration significantly increased DIG renal clearance in rats. Surprisingly, BUP significantly inhibited r-Oatp4c1 mediated transport of [(3) H]-DIG at clinically relevant unbound plasma concentrations of BUP or those observed in rat study, while HBUP or TBUP did not. These data support our hypothesis that at clinical relevant plasma concentrations, BUP and its metabolites activate H-OATP4C1 mediated DIG tubular secretion, and could possibly explain the increase in DIG renal clearance produced by BUP. While BUP increased DIG renal clearance in the rat, it appeared to do so by inhibiting r-Oatp4c1-mediated DIG renal reabsorption. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 01/2014;
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    ABSTRACT: EPZ-5676 ((2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL-rearranged leukemias. In this report, we describe the preclinical pharmacokinetics and metabolism of EPZ-5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following IV and PO administration; EPZ-5676 had moderate to high clearance, low oral bioavailability with a steady-state volume of distribution 2-3 fold higher than total body water. EPZ-5676 showed biexponential kinetics following IV administration, giving rise to terminal t1/2 of 1.1, 3.7 and 13.6 h in mouse, rat and dog respectively. Corresponding in vitro ADME parameters were also studied and utilized for in vitro - in vivo extrapolation purposes. There was good agreement between microsomal clearance and in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to fu-corrected GFR and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ-5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N-dealkylated product (M4) as well as an N-oxide (M6). This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 01/2014;
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    ABSTRACT: Diclofenac instillation has been widely used in cataract surgery to prevent postoperative inflammation. Since diclofenac strongly binds to albumin in the circulation, it does not have a sufficient effect on patients in whom diclofenac strongly binds to albumin in the aqueous humor. To decrease in diclofenac binding and increase free diclofenac levels are necessary in these patients. We investigated the binding of diclofenac to albumin in the aqueous humor. In a diclofenac binding assay with albumin in the aqueous humor of individual patients, diclofenac was extracted from aliquots of the aqueous humor, and its total levels were measured using ultra high performance liquid chromatography (UHPLC). Free diclofenac levels were measured using ultrafiltration and UHPLC. The albumin-binding fraction of diclofenac was 0.8 or higher in the aqueous humor of some patients. Ibuprofen significantly inhibited diclofenac binding to site II of albumin in mimic aqueous humor, but not in pooled aqueous humor. This difference may have been due to the weak binding of diclofenac to site II in pooled aqueous humor. We used flurbiprofen instead of diclofenac. Flurbiprofen has been shown to bind more strongly than diclofenac to the same site of albumin. Thus, we investigated the inhibitory effect of ibuprofen on the binding of flurbiprofen to albumin in pooled aqueous humor. The results indicated that ibuprofen significantly inhibited the flurbiprofen binding. An effective diclofenac administration method may be established for clinical application by the instillation of an appropriate inhibitor of binding to albumin site II. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 01/2014;
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    ABSTRACT: A cocktail approach can detect the activities of multiple cytochrome P450 (CYP) isoforms following the administration of multiple CYP-specific substrates in a single experiment. In this study, we aimed to develop a simultaneous and comprehensive in vivo analysis of CYP activity in rats. Rats received oral administration of losartan (10 mg/kg) and omeprazole (40 mg/kg). Caffeine (1 mg/kg), dextromethorphan (10 mg/kg), and midazolam (10 mg/kg) were administered 15 min later. In the drug-interaction phase, the rats were orally treated with dexamethasone (80 mg/kg) 24 h before, or with ketoconazole (10 mg/kg), fluvoxamine (100 mg kg), or fluconazole (10 mg/kg) 1 h before, the administration of cocktail drugs. The concentrations of the drugs and their metabolites were determined by LC/MS/MS. Plasma concentrations of 5 CYP substrates and their metabolites were simultaneously evaluated after the oral drug administration. Fluvoxamine and fluconazole significantly increased Cmax and AUC of caffeine, and AUC of omeprazole and midazolam. Dexamethasone significantly increased Cmax and AUC of losartan, while it decreased Cmax of midazolam. Ketoconazole showed no significant effect on the pharmacokinetic parameters of the tested drugs. In conclusion, a cocktail approach was developed for simultaneous and comprehensive analysis of the activities of multiple CYP isoforms in rats. In this approach, the effects of inhibitors and an inducer of various CYP isoforms were examined. Although further studies are necessary to predict effects in humans, this approach may be expected to serve as a convenient method for detecting drug-drug interactions in rats. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 01/2014;
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    ABSTRACT: Clenbuterol is a long-acting β2-adrenoceptor agonist and bronchodilator that is used for treatment of asthma, but the desired activities reside almost exclusively in the (-)-R-enantiomer. Here, we examined enantioselectivity in the disposition of clenbuterol following administration of clenbuterol racemate to rats. Concentrations of clenbuterol enantiomers in plasma, urine, and bile were determined by LC-MS/MS assay with a Chirobiotic T column. This method was confirmed to show high sensitivity, specificity, and precision, and clenbuterol enantiomers in 0.1-mL volumes of plasma were precisely quantified at concentrations as low as 0.25 ng/mL. The pharmacokinetic profiles of clenbuterol enantiomers following intravenous and intraduodenal administration of clenbuterol racemate (2 mg/kg) in rats were significantly different. The distribution volume of (-)-R-clenbuterol (9.17 L/kg) was significantly higher than that of (+)-S-clenbuterol (4.14 L/kg). Total body clearance of (-)-R-clenbuterol (13.5 mL/min/kg) was significantly higher than that of the (+)-S-enantiomer (11.5 mL/min/kg). An in-situ absorption study in jejunal loops showed no difference in residual amount between the (-)-R- and (+)-S-enantiomers. Urinary clearance was the same for the two enantiomers, but biliary excretion of (-)-R-clenbuterol was higher than that of the (+)-S-enantiomer. The fractions of free (non-protein-bound) (-)-R- and (+)-S-clenbuterol in rat plasma were 48.8, and 33.1%, respectively. These results indicated that there are differences in distribution and excretion of the clenbuterol enantiomers, and these may be predominantly due to enantioselective protein binding. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 12/2013;
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    ABSTRACT: Periplocymarin, a cardiac glycoside isolated from Periploca sepium (P. sepium) and Periploca graeca (P. graeca), is a potential anti-cancer compound. The aim of the study is to investigate the potential for periplocymarin to interact with P-glycoprotein (P-gp) and inhibit cytochrome P450's known to be expressed in the human small intestine. The in vitro and in situ permeability of periplocymarin were studied using Madin-Darby canine kidney (MDCK-II-WT) cells transfected with or without the human multidrug resistance (MDR1) gene and the single-pass perfused rat intestinal model. The cell system exhibited high functional activity and a net efflux ratio (NER) of 4.32 after transport of Rhodamine 123 (R123) (the P-gp substrate). Periplocymarin is highly permeable (Papp > 10 × 10-6 cm/s; Peff(rat) > 5.09 × 10-5 cm/s) and independent of P-gp influences. The NER at 100 μM periplocymarin (0.8) was unchanged in the presence of cyclosporine A (a non-specific P-gp inhibitor) (0.82). In the single-pass intestinal model, the Peff (rat) of 5 µg/mL periplocymarin (5.490 × 10-5 cm/s) did not change in the presence of cyclosporine A (5.394 × 10-5 cm/s). In the R123-inhibition assay, periplocymarin did not competitively inhibit P-gp. The inhibitory potential of periplocymarin on Cytochrome P450 (CYP450s) was also studied. Periplocymarin (5, 50 μM) did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Thus, periplocymarin is unlikely to encounter drug-drug interactions with P-gp and CYP450s. Peripolcymarin could be taken forward for further studies in drug development to test bioavailability, Phase II enzyme interactions and additional transporter interactions. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 12/2013;
  • Biopharmaceutics & Drug Disposition 12/2013; 34(9):475-6.
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    ABSTRACT: We investigated the in vitro metabolic stability and transport mechanism of TM-25659, a novel TAZ modulator, in human hepatocytes and human liver microsomes (HLMs) based on the preferred hepatobiliary elimination in rats. In addition, we also evaluated in vitro transport mechanism and transporter-mediated drug-drug interactions using oocytes and MDCKII cells overexpressing clinically important drug transporters. After 1 h incubation in HLMs, 92.9 ± 9.5% and 95.5 ± 11.6% of initial TM-25659 remained in the presence of NADPH and UDPGA, respectively. The hepatic uptake of TM-25659 readily accumulated in human hepatocytes at 37 °C (i.e. 6.7-fold greater than that at 4 °C), in which drug transporters such as OATP1B1 and OATP1B3 were involved. TM-25659 had a significantly greater basal to apical transport rate (5.9-fold) than apical to basal transport rate in the Caco-2 cell monolayer, suggesting the involvement of an efflux transport system. Further studies using inhibitors of efflux transporters and overexpressing cells revealed that MRP2 was involved in the transport of TM-25659. These results, taken together, suggested that TM-25659 can be actively influxed into hepatocytes and undergo biliary excretion without substantial metabolism. Additionally, TM-25659 inhibited the transport activities of OATP1B1 and OATP1B3 with IC50 values of 36.3 and 25.9 μM, respectively. TM-25659 (100 μM) increased the accumulation of probe substrate by 160% and 213%, respectively, through the inhibiton of efflux function of P-gp and MRP2. In conclusion, OATP1B1, OATP1B3, P-gp, and MRP2 might be major transporters responsible for the pharmacokinetics and drug-drug interaction of TM-25659, although their contribution to in vivo pharmacokinetics need to be further investigated. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2013;
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    ABSTRACT: Sirolimus, an immunosuppressive drug used to prevent organ rejection after renal transplantation, has a narrow therapeutic index and a large inter-individual variability of pharmacokinetics. The aim of this study was to analyze the dose-normalized trough blood concentrations (C0 /D ratio) of sirolimus in patients with different genotypes and attempted to investigate the possible associations between ABCB1/CYP3A5 genotypes and sirolimus dose requirements in Chinese renal transplant recipients. Blood samples were collected from 85 Chinese renal transplant recipients who were treated with sirolimus for at least 3 months and polymorphisms of the ABCB1 and CYP3A5 were determined by SNaPShot multiplex assay. The blood concentrations of sirolimus were determined with HPLC. A significant allele-dependent effect was observed between the CYP3A5*3 polymorphism and the C0 /D ratio of sirolimus. The patients bearing at least one CYP3A5*1 allele have lower sirolimus C0 /D ratio compared to those with a homozygous CYP3A5*3 genotype (p < 0.05). No significant differences of sirolimus C0 /D ratios were observed among various ABCB1 1236C > T, 2677G > T/A and 3435C > T genotype groups. However, haplotype analysis including ABCB1 1236C > T, 2677G > T/A and 3435C > T SNPs showed that mean sirolimus C0 /D of subjects carrying the CGC/CGC diplotype was about 30% lower compared with those carrying the CGC/TTT or TTT/TTT diplotype, whether or not they express the CYP3A5 (p < 0.05). These results demonstrated that the haplotype of ABCB1 might be a better index for the prediction of sirolimus blood concentration than single SNPs. Genotyping of ABCB1 and CYP3A5 might help to optimize the individualized sirolimus treatment for Chinese renal transplant recipients. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2013;
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    ABSTRACT: Quercetin-3-rhamnoglucoside (rutin) has a wide spectrum of biochemical and pharmacological activities. Rutin is mainly absorbed in its unmetabolized form. Organic anion transporting polypeptide (OATP) 2B1 is a major uptake transporter in the intestine. Thus, it is important for prevention of adverse events to understand drug interaction mediated by OATP2B1 in the absorption process. In this study, we assessed the effect of rutin on transport by OATP2B1. Rutin stimulated the uptake of estrone-3-sulfate (E-3-S), taurocholic acid (TCA), cholic acid (CA) and rosuvastatin by OATP2B1, but p-coumaric acid and ferulic acid did not stimulate. The EC50 of rutin for transport by OATP2B1 was 2.32 μM. The Km value of E-3-S for OATP2B1 in the presence of rutin (9.21 μM) was almost the same as that in the absence of rutin (8.53 μM). On the other hand, Vmax of E-3-S transport by OATP2B1 in the presence of rutin (270 pmol/mg protein/min) was 1.2-fold higher than that in the absence of rutin (218 pmol/mg protein/min). Moreover, the expression level of OATP2B1 on the cell membrane was increased by treatment with rutin for 5 min without alteration of total OATP2B1 expression level. Moreover, the increase in localization of OATP2B1 at the cell surface was detected by the immnocytochemistry. The stimulatory effect of rutin is a little weakness but may affect the absorption of OATP2B1 substrate, because rutin is daily taken in from foods and its intestinal concentration would be reached to the stimulatory range of OATP2B1. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2013;
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    ABSTRACT: Factor VIII (FVIII) is an important cofactor in the blood coagulation cascade and its deficiency or dysfunction causes Hemophilia A (HA), a bleeding disorder. Replacement with recombinant FVIII is limited by a short half-life and the development of inhibitory antibodies. We have developed a phosphatidylinositol (PI) containing lipid nanoparticle that, when associated with FVIII, reduces immunogenicity and prolongs circulation of the therapeutic protein in HA mice. Here,we conducted a multiple dose levelpharmacokinetic (PK)study of human free FVIII and its FVIII-PI complex overa clinically relevant range of doses (20, 40, and 200 IU/kg) in HA mice to investigate linearity of the PK and to determine if reduced catabolism of FVIII following association with PI particles, previously only observed in the terminal phase following 400 IU/kg,could be extendable over a range of doses. Our findings suggest that the disposition of FVIII is best characterized by a two-compartment model with saturableMichaelis-Mentenelimination. Spontaneous complexation of FVIII with PI particles significantlyincreases plasma survival of the proteinat 20 and 40 IU/kg doses. Human simulations at 40 IU/kg project anincrease in terminal half-life and time to reach a minimum therapeutic threshold of 0.01 IU/mL of 5.4 h and 40 h respectively compared to free FVIII. Formulation with PI containing lipid particles may represent a viable delivery strategy for improving FVIII therapy. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2013;
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    ABSTRACT: Quantitative structure-activity relationship (QSAR) studies and mechanistic mathematical modeling approaches have been independently employed for analyzing and predicting the transport and distribution of small molecule chemical agents in living organisms. Both of these computational approaches have been useful to interpret experiments measuring the transport properties of small molecule chemical agents, in vitro and in vivo. Nevertheless, mechanistic cell-based pharmacokinetic models have been especially useful to guide the design of experiments probing the molecular pathways underlying small molecule transport phenomena. Unlike QSAR models, mechanistic models can be integrated from microscopic to macroscopic levels, to analyze the spatiotemporal dynamics of small molecule chemical agents from intracellular organelles to whole organs, well beyond the experiments and training data sets upon which the models are based. Based on differential equations, mechanistic models can also be integrated with other differential equations-based systems biology models of biochemical networks or signaling pathways. Although the origin and evolution of mathematical modeling approaches aimed at predicting drug transport and distribution has occurred independently from systems biology, we propose that the incorporation of mechanistic cell-based computational models of drug transport and distribution into a systems biology modeling framework is a logical next-step for the advancement of systems pharmacology research. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2013;
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    ABSTRACT: The drug development industry faces multiple challenges in the realization of safe effective drugs. Computational modeling approaches can be used to support these efforts. One approach, mechanistic modeling, is new to the realm of drug safety. It holds the promise of not only predicting toxicity for novel compounds but also illuminating the mechanistic underpinnings of toxicity. To increase the scientific community's familiarity with mechanistic modeling in drug safety, this article seeks to provide perspective on the type of data used, how they are used, and where they are lacking. Examples are derived from the development of the DILIsym® model, a mechanistic model of drug-induced liver injury (DILI). The DILIsym® model simulates the mechanistic interactions and events from compound administration through the progression of liver injury and regeneration. Modeling mitochondrial toxicity illustrates the type and use of in vitro data to represent biological interactions, as well as insights on key differences between in vitro and in vivo conditions. Modeling bile acid toxicity illustrates a case where the over-arching mechanism is well-accepted, but many mechanistic details are lacking. Modeling was used to identify measurements predicted to strongly impact toxicity. Finally, modeling innate immune responses illustrates the importance of time-series data, particularly in the presence of positive and negative feedback loops, as well as the need for data from different animal species for better translation. These concepts are germane to most mechanistic models, although the details will vary. The use of mechanistic models is expected to improve the rational design of new drugs. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 11/2013;
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    ABSTRACT: In this study, an in vitro experimental system for evaluating the inhibitory effect of investigational drugs on the P-glycoprotein (P-gp, MDR1)-mediated transport of tacrolimus (FK506) was developed using LLC-PK1-MDR1 and LLC-PK1 wild-type (control) cells. The amount of tacrolimus (concentrations: 1 and 5 μm) transported into P-gp-expressing and control cells increased with time in both the apical-to-basal and basal-to-apical directions at incubation times ranging from 40 min to 2 h. The corrected apparent permeability (Papp) ratio, obtained by dividing the Papp ratio in P-gp-expressing cells by that in the control cells, ranged from 2.6 to 5.3, showing significant differences in the transport of tacrolimus between the P-gp-expressing cells and the control cells. This system was then subsequently used to examine the P-gp transport of tacrolimus in the presence of verapamil (30 μm), a model inhibitor for P-gp-mediated transport activity. The corrected Papp ratios in the absence and presence of verapamil were 6.9 and 0.8, respectively. Data derived in the present study suggest that our developed system has the ability to detect a sufficient difference in the P-gp transport of tacrolimus between P-gp-expressing and control cells, and we therefore believe our system to be suitable for use in evaluating the inhibitory effects of investigational drugs on the P-gp-mediated transport of tacrolimus. Copyright © 2013 John Wiley & Sons, Ltd.
    Biopharmaceutics & Drug Disposition 11/2013;

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