title: Differential genotype dependent inhibition of CYP2C9 in humans.
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.
authors: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Vikas
authors: V
authors: Kumar
authors: Richard C
authors: RC
authors: Brundage
authors: William S
authors: WS
authors: Oetting
authors: Ilo E
authors: IE
authors: Leppik
authors: Timothy S
authors: TS
authors: Tracy
mesh_terms: D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D005480:Flurbiprofen / Q000493:pharmacokinetics / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D012016:Reference Values
chemical_list: D004791:Enzyme Inhibitors; D005480:Flurbiprofen; D015725:Fluconazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases