In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.

摘要: In-vitro studies were conducted to assess the impact of CYP2C9 genotype on metabolism (methyl hydroxylation) and pharmacokinetics celecoxib, a novel cyclooxygenase-2 inhibitor substrate. When compared cDNA-expressed wild-type (CYP2C9*1), Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% 90% in presence recombinant CYP2C9*2 CYP2C9*3, respectively. These data indicated that amino acid substitution at position 359 (Ile Leu) elicited more pronounced effect than did 144 (Arg Cys). The also decreased microsomes livers genotyped CYP2C9*1/*2 (47% decrease, mean two livers), or CYP2C9*1/*3 (59% one liver). In all cases, these changes largely reflective decrease Vmax, with minimal change Km. Based simulations in-vitro obtained proteins, it anticipated (as much as five-fold increase plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) subjects heterozygous homozygous (Cys144) CYP2C9*3 (Leu359) allele. subsequent clinical study, AUC increased approximately 2.2-fold (range, 1.6-3-fold) CYP2C9*3/*3 subject receiving single oral dose (200 mg) drug. contrast, there no significant CYP2C9*1/*2.