Received for publication January 7, 2008.
Revised March 27, 2008.
Accepted for publication March 27, 2008.

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Abstract

The effect 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 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, eleven control subjects (CYP2C9*1/*1), nine heterozygous and two 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 fluconazole for seven days using an open, randomized, cross-over 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 400mg fluconazole for seven days. Changes in flurbiprofen apparent oral clearance after fluconazole co-administration were gene-dose dependent, with virtually no change occurring in *3/*3 subjects. Analysis of fractional clearances suggested that 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 co-administration of inhibitors.

Key words: CYP inhibition, CYP2C, cytochrome P450, drug interactions, human CYP enzymes