Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele

Kidd, Robert S.; Straughn, Arthur B.; Meyer, Marvin C.; Blaisdell, Joyce; Goldstein, Joyce A.; Dalton, James T.

doi:10.1097/00008571-199902000-00010

Cited by 153 publications

(81 citation statements)

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“…Similar reductions in metabolizing capacity were observed in patients heterozygous for the Leu359 allele and receiving phenytoin (Hashimoto et al, 1996). The homozygous Leu359 allele has been associated with the poor metabolizer phenotype for tolbutamide (Sullivan-Klose et al, 1996;Bhasker et al, 1997), warfarin (Steward et al, 1997), phenytoin and glipizide (Kidd et al, 1999), and losartan (Spielberg et al, 1996). With respect to the Glu360 variant (CYP2C9*5), Dickmann et al (2001) reported that this amino acid substitution increases the K m for the in vitro metabolism of S-warfarin, diclofenac, and lauric acid, with more modest effects on V max .…”

mentioning

confidence: 64%

Polymorphic Variants (CYP2C93 and CYP2C95) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

et al. 2002

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:CYP2C9 wild-type protein has been shown to exhibit atypical kinetic profiles of metabolism that may affect in vitro-in vivo predictions made during the drug development process. Previous work suggests a substrate-dependent effect of polymorphic variants of CYP2C9 on the rate of metabolism; however, it is hypothesized that these active site amino acid changes will affect the kinetic profile of a drug's metabolism as well. To this end, the kinetic profiles of three model CYP2C9 substrates (flurbiprofen, naproxen, and piroxicam) were studied using purified CYP2C9*1 (wild-type) and variants involving active site amino acid changes, including the naturally occurring variants CYP2C9*3 (Leu359) and CYP2C9*5 (Glu360) and the man-made mutant CYP2C9 F114L. CYP2C9*1 (wild-type) metabolized each of the three compounds with a distinctive profile reflective of typical hyperbolic (flurbiprofen), biphasic (naproxen), and substrate inhibition (piroxicam) kinetics. CYP2C9*3 metabolism was again hyperbolic for flurbiprofen, of a linear form for naproxen (no saturation noted), and exhibited substrate inhibition with piroxicam. CYP2C9*5-mediated metabolism was hyperbolic for flurbiprofen and piroxicam but linear with respect to naproxen turnover. The F114L mutant exhibited a hyperbolic kinetic profile for flurbiprofen metabolism, a linear profile for naproxen metabolism, and a substrate inhibition kinetic profile for piroxicam metabolism. In all cases except F114L-mediated piroxicam metabolism, turnover decreased and the K m generally increased for each allelic variant compared with wild-type enzyme. It seems that the kinetic profile of CYP2C9-mediated metabolism is dependent on both substrate and the CYP2C9 allelic variant, thus having potential ramifications on drug disposition predictions made during the development process.

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confidence: 64%

Polymorphic Variants (CYP2C93 and CYP2C95) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

et al. 2002

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“…Various case reports have suggested that the biotransformation of drugs such as S-warfarin 22,23 and phenytoin 24,25 are severely compromised in individuals who are homozygous for CYP2C9*3. The frequency of the homozygous CYP2C9*3 genotype is relatively small (approximately 1-2%) in Caucasians and this genotype has not been detected in other populations (eg Ethiopians).…”

Section: Pc Ho Et Almentioning

confidence: 99%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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The present study investigated the effect of cytochrome P450 2C9 (CYP2C9) genetic polymorphism on the biotransformation of valproic acid (VPA) to its hepatotoxic metabolite, 4-ene-VPA, and compared that to the formation of the inactive 4-OH-VPA and 5-OH-VPA. cDNA-expressed CYP2C9*2 and CYP2C9*3 variants were less efficient than the CYP2C9*1 wild type in catalyzing the formation of these metabolites, as assessed by the ratio of Vmax and apparent Km (in vitro intrinsic clearance). The reduced efficiency by CYP2C9*2 was due to a reduced Vmax, whereas, in the case of CYP2C9*3, it was the result of increased apparent Km. The formation rates of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA in human liver microsomes were reduced by 29, 28, and 31%, respectively, in samples with one mutated CYP2C9 allele, and by 61, 73, and 58%, respectively, in samples with two mutated CYP2C9 alleles. Overall, the homozygote and heterozygote CYP2C9*2 and CYP2C9*3 genotypes may compromise hepatic VPA biotransformation.

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“…Their results indicated that the I359L exchange significantly reduces the catalytic activity with all CYP2C9-mediated substrates studied, although the extent of the reduction in activity and kinetic parameters varied between different substrates. Interestingly Kidd et al [39] reported a male Caucasian, homozygous for CYP2C9*3, who poorly metabolized phenytoin and glipizide/ tolbutamide. This study establishes that the I359L mutation is responsible for the poor metabolizer phenotype.…”

Section: Discussionmentioning

confidence: 99%

Cloning of cytochrome P-450 2C9 cDNA from human liver and its expression in CHL cells

Zhu

Yu²,

Li³

et al. 2002

WJG

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AIM: Using bacterial, yeast, or mammalian cell expressing a human drug metabolism enzyme would seem good way to study drug metabolism-related problems. Human cytochrome P-450 2C9(CYP2C9) is a polymorphic enzyme responsible for the metabolism of a large number of clinically important drugs. It ranks among the most important drug metabolizing enzymes in humans. In order to provide a sufficient amount of the enzyme for drug metabolic research, the CYP2C9 cDNA was cloned and expressed stably in CHL cells.

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Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele

Cited by 153 publications

References 0 publications

Polymorphic Variants (CYP2C93 and CYP2C95) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

Polymorphic Variants (CYP2C93 and CYP2C95) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Cloning of cytochrome P-450 2C9 cDNA from human liver and its expression in CHL cells

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Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele

Cited by 153 publications

References 0 publications

Polymorphic Variants (CYP2C9*3 and CYP2C9*5) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

Polymorphic Variants (CYP2C9*3 and CYP2C9*5) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Cloning of cytochrome P-450 2C9 cDNA from human liver and its expression in CHL cells

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Polymorphic Variants (CYP2C93 and CYP2C95) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

Polymorphic Variants (CYP2C93 and CYP2C95) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles