Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine

Lindh, Jonatan D.; Annas, Anita; Meurling, Lennart; Al‐Shurbaji, Ayman

doi:10.1007/s00228-003-0627-x

Cited by 36 publications

(29 citation statements)

References 11 publications

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“…Similarly, studies have been conducted in extensive versus poor metabolizers of CYP2D6 and the extent of drug-drug interactions was compared. These studies have consistently reported a greater degree of inhibition of wild-type CYP2D6 enzyme compared with variant forms of CYP2D6 (Hamelin et al, 2000;Lessard et al, 2001;LLerena et al, 2001;Lindh et al, 2003). The variant alleles of CYP2C19, as well as those of CYP2D6, in the above studies cause either a splicing defect or a frame shift resulting in either premature termination of translation or a truncated protein.…”

Section: Discussionmentioning

confidence: 81%

“…However, genetic polymorphisms in drug-metabolizing enzymes are not routinely evaluated for their impact on drug interactions during clinical studies. Genotype-dependent inhibition has been demonstrated with CYP2D6 and CYP2C19 genetic polymorphisms (Hamelin et al, 2000;Lessard et al, 2001;LLerena et al, 2001;Lindh et al, 2003; Yasui-Furukori et al, 2004a,b;Uno et al, 2006), but these polymorphisms resulted in expression of inactive proteins that should not be subject to inhibition. No clinical studies have explored the effect of single nucleotide polymorphisms (SNPs) resulting in reduced activity enzymes (e.g., CYP2C9*3) and their effect on the degree of inhibition interactions observed.…”

Section: Introductionmentioning

confidence: 99%

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Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Kumar

Brundage²,

Oetting³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The effects of genetic polymorphisms in drug-metabolizing enzymes (e.g., CYP2C9*3) on drug clearance have been well characterized but much less is known about whether these polymorphisms alter susceptibility to drug-drug interactions. Previous in vitro work has demonstrated that genotype-dependent inhibition of CYP2C9 mediated flurbiprofen metabolism, suggesting the possibility of genotype-dependent inhibition interactions in vivo. In the current study, flurbiprofen was used as a probe substrate and fluconazole as a prototypical inhibitor to investigate whether genotype-dependent inhibition of CYP2C9 occurs in vivo. From 189 healthy volunteers who were genotyped for CYP2C9 polymorphisms, 11 control subjects (CYP2C9*1/*1), 9 heterozygous and 2 homozygous for the CYP2C9*3 allele participated in the pharmacokinetic drug interaction study. Subjects received a single 50-mg oral dose of flurbiprofen alone or after administration of either 200 or 400 mg of fluconazole for 7 days using an open, randomized, crossover design. Flurbiprofen and fluconazole plasma concentrations along with flurbiprofen and 4-hydroxyflurbiprofen urinary excretion were monitored. Flurbiprofen apparent oral clearance differed significantly among the three genotype groups (p < 0.05) at baseline but not after pretreatment with 400 mg of fluconazole for 7 days. Changes in flurbiprofen apparent oral clearance after fluconazole coadministration were gene dose-dependent, with virtually no change occurring in *3/*3 subjects. Analysis of fractional clearances suggested that the fraction metabolized by CYP2C9, as influenced by genotype, determined the degree of drug interaction observed. In summary, the presence of CYP2C9*3 alleles (either one or two alleles) can alter the degree of drug interaction observed upon coadministration of inhibitors.The cytochrome P450 (P450) superfamily of enzymes plays an important role in the oxidation of numerous xenobiotics, with CYP2C9 accounting for 10 to 20% of the P450 protein content in human liver. CYP2C9 has been reported to catalyze approximately 20% of P450-mediated drug oxidation reactions (Shimada et al., 1994;Rendic and Dicarlo, 1997;Miners and Birkett, 1998), including agents such as nonsteroidal anti-inflammatory drugs, tolbutamide, losartan, and the narrow therapeutic index drugs warfarin and phenytoin (Rettie et al., 1992;Stearns et al., 1995;Tracy et al., 1995;Bajpai et al., 1996;Miners and Birkett, 1996;Hamman et al., 1997;Niemi et al., 2002;Yan et al., 2005). To date, 30 CYP2C9 allelic variants located within the coding region have been reported (http://www.imm.ki.SE/CYPalleles). In particular, the *3 allele (Ile 359 Leu), which is expressed at an allele frequency of 15% (Lee et al., 2002), results in significantly reduced oral clearance for several CYP2C9 substrates (Aithal et al., 1999;Lee et al., 2003b;Vianna-Jorge et al., 2004;Guo et al., 2005;Perini et al., 2005) and has been associated with an increased frequency of adverse events after warfarin or phenytoin administration (Kidd et al., ...

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Kumar

Brundage²,

Oetting³

et al. 2008

Drug Metab Dispos

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“…For example, fluoxetine is primarily metabolized via N-demethylation by CYP2D6, 2C9, and 3A (von Moltke et al, 1997;Margolis et al, 2000), paroxetine by demethylenation of its methylenedioxy group by CYP2D6 (Bloomer et al, 1992), venlafaxine by O-demethylation by CYP2D6 (Otton et al, 1996;Fogelman et al, 1999), and citalopram by CYP3A4-, 2D6-, and 2C19-catalyzed N-demethylation (Kobayashi et al, 1997;von Moltke et al, 1999von Moltke et al, , 2001Olesen and Linnet, 1999). As such, these drugs have been shown to be subject to drug interactions by various inhibitors of cytochrome P450 enzymes such as quinidine and ketoconazole (Lessard et al, 1999;Eap et al, 2003;Lindh et al, 2003). Also, some of these agents have been shown to exhibit substantial differences in pharmacokinetics in subjects who lack CYP2D6 or CYP2C19, such as fluoxetine, paroxetine, and venlafaxine (Hamelin et al, 1996;Lessard et al, 1999;Liu et al, 2001;Charlier et al, 2003;Lindh et al, 2003;Yu et al, 2003).…”

mentioning

confidence: 99%

“…As such, these drugs have been shown to be subject to drug interactions by various inhibitors of cytochrome P450 enzymes such as quinidine and ketoconazole (Lessard et al, 1999;Eap et al, 2003;Lindh et al, 2003). Also, some of these agents have been shown to exhibit substantial differences in pharmacokinetics in subjects who lack CYP2D6 or CYP2C19, such as fluoxetine, paroxetine, and venlafaxine (Hamelin et al, 1996;Lessard et al, 1999;Liu et al, 2001;Charlier et al, 2003;Lindh et al, 2003;Yu et al, 2003).…”

mentioning

confidence: 99%

Sertraline Is Metabolized by Multiple Cytochrome P450 Enzymes, Monoamine Oxidases, and Glucuronyl Transferases in Human: An in Vitro Study

Obach¹,

Cox²,

Tremaine³

2004

Drug Metab Dispos

178

139

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ABSTRACT:The oxidative and conjugative metabolism of sertraline was examined in vitro to identify the enzymes involved in the generation of N-desmethyl, deaminated, and N-carbamoyl-glucuronidated metabolites in humans. In human liver microsomes, sertraline was N-demethylated and deaminated by cytochrome P450 (P450) enzymes with overall K m values of 98 and 114 M, respectively, but the intrinsic clearance for N-demethylation was approximately 20-fold greater than for deamination. Using P450 isoform-selective inhibitors and recombinant heterologously expressed enzymes, it was demonstrated that several P450 enzymes catalyzed sertraline N-demethylation, with CYP2B6 contributing the greatest extent, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. For deamination, data supported a role for CYP3A4 and CYP2C19. Purified human monoamine oxidases A and B also catalyzed sertraline deamination with comparable K m values (230-270 M). Monoamine oxidase B catalyzed the reaction approximately 3-fold faster than did monoamine oxidase A. Sertraline N-carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO 2 atmosphere (K m ‫؍‬ 50 M) and was catalyzed at the fastest rate by recombinant human UGT2B7. The observation that multiple enzymes appear to be involved in sertraline metabolism suggests that there should be no single agent that could substantially alter the pharmacokinetics of sertraline, nor should there be any single drug-metabolizing enzyme genetic polymorphism (e.g., CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline.

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“…Recently, Lindh et al (2003) carried out an interesting clinical investigation to evaluate the role of CYP3A4 inhibition on the disposition of venlafaxine in EMs (n = 14) and PMs (n = 7) of CYP2D6 isozyme. The exposure (AUC) ratio of O-desmethylvenlafaxine to venlfaxine was well correlated with the debrisoquine metabolic ratio, suggesting a clear role of CYP2D6 isozyme in the pharmacokinetic disposition of venlafaxine.…”

Section: Venlafaxinementioning

confidence: 99%

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

Srinivas

2006

Biomedical Chromatography

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The concepts of drug development have evolved over the last few decades. Although number of novel chemical entitities belonging to varied classes have made it to the market, the process of drug development is challenging, intertwined as it is with complexities and uncertainities. The intention of this article is to provide a comprehensive review of novel chemical entities (NCEs) that are substrates to cytochrome P450 (CYP) 2D6 isozyme. Topics covered in this review aim: (1) to provide a framework of the importance of CYP2D6 isozyme in the biotransformation of NCEs as stand-alones and/or in conjunction with other CYP isozymes; (2) to provide several case studies of drug disposition of important drug substrates, (3) to cover key analytical perspectives and key assay considerations to assess the role and involvement of CYP2D6, and (4) to elaborate some important considerations from the development point of view. Additionally, wherever applicable, special emphasis is provided on chiral drug substrates in the various subsections of the review.

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Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine

Abstract: Ketoconazole consistently affected the disposition of venlafaxine in EMs of debrisoquine while the response in PMs was erratic. The precise mechanisms underlying this interaction remain to be elucidated.

Cited by 36 publications

References 11 publications

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Sertraline Is Metabolized by Multiple Cytochrome P450 Enzymes, Monoamine Oxidases, and Glucuronyl Transferases in Human: An in Vitro Study

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

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