In Vitro Approaches to Predicting Drug Interactions In Vivo

Moltke, Lisa L. von; Greenblatt, David J.; Schmider, Jürgen; Wright, Christopher; Harmatz, Jerold S.; Shader, Richard I.

doi:10.1016/s0006-2952(97)00239-6

Cited by 171 publications

(139 citation statements)

References 82 publications

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“…Our findings contradict these predictions and show that extrapolation of in vitro results to the in vivo situation remains speculative. Lack of correlation between in vitro and in vivo studies with botanical extracts is not unexpected given the myriad limitations recognized for in vitro models as predictors of drug interactions in vivo (von Moltke et al, 1998). Often, such discrepancies can be traced to basic pharmaceutics issues, including inadequate dosage form disintegration and/or dissolution.…”

Section: Discussionmentioning

confidence: 99%

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

et al. 2006

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ABSTRACT:Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC) (0-3) , AUC (0-24) , C max, CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC (0-3) , AUC (0-24) , CL/F, t 1/2 , and C max , whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C max (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

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Section: Discussionmentioning

confidence: 99%

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

et al. 2006

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“…In one study, valproic acid at a serum concentration of about 400 mM reduced the systemic clearance of unbound phenytoin by 23% [2]. This decrease is at least three times larger than what would be expected on the basis of unbound valproic acid concentrations (assuming a 10% unbound fraction [14]) and a K i of 600 mM for CYP2C9 [30]. Thus, the concentrations of valproic acid to which the enzyme is exposed in the liver may be even higher than its unbound plasma concentrations.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

Xia

Wang

Kivistö

et al. 2001

Brit J Clinical Pharma

141

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Aims To evaluate the potency and speci®city of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes. Methods Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform speci®c marker reactions were measured: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S-mephenytoin 4k-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1) and midazolam 1k-hydroxylase (CYP3A4). Results Valproic acid competitively inhibited CYP2C9 activity with a K i value of 600 mM. In addition, valproic acid slightly inhibited CYP2C19 activity (K i =8553 mM, mixed inhibition) and CYP3A4 activity (K i =7975 mM, competitive inhibition).The inhibition of CYP2A6 activity by valproic acid was time-, concentration-and), consistent with mechanism-based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed. Conclusions Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co-administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in signi®cant drug interactions.

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“…Data from in vitro kinetic studies are widely used to predict in vivo hepatic clearance (CL H ), extraction ratio, and drug-drug interaction potential for compounds metabolized by cytochrome P450 (P450) and UGT enzymes using in vitro-in vivo extrapolation (IV-IVE) approaches (Houston 1994;Iwatsubo et al, 1997;von Moltke et al, 1998;Obach 1999;Proctor et al, 2004;Riley et al, 2005;Hosea et al, 2009). Typically, however, IV-IVE generally results in underprediction of CL H and the magnitude of inhibitory drug-drug interactions (Boase and Miners, 2002;Ito et al, 2004;Ito and Houston, 2005;Miners et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

Wattanachai¹,

Tassaneeyakul²,

Rowland³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Long-chain unsaturated fatty acids inhibit several cytochrome P450 and UDP-glucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4, and UGT2B7. Bovine serum albumin (BSA) enhances these cytochrome P450 and UGT activities by sequestering fatty acids that are released from membranes, especially with human liver microsomes (HLM) as the enzyme source. Here, we report the effects of BSA on CYP1A2-catalyzed phenacetin (

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In Vitro Approaches to Predicting Drug Interactions In Vivo

Cited by 171 publications

References 82 publications

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

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