Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo.

The effect of cytochrome P450 (CYP) 2C9 polymorphisms on the stereoselective biotransformation of the oral anticoagulant phenprocoumon (PPC) to inactive, monohydroxylated metabolites was studied in vitro and in vivo. In human liver microsomes, the (S)-7-hydroxylation--being the major metabolic pathway--was significantly compromised in a gene-dose-dependent manner in samples expressing the CYP2C92 or CYP2C93 allele. The CYP2C93/3 genotype corresponded to an almost fourfold lower (S)-7-hydroxylation rate than CYP2C91/1 (wild-type). The intrinsic clearance of human recombinant CYP2C92 and CYP2C93 for the (S)-7-hydroxylation was 28.9 and 50.9% lower than of CYP2C91, respectively. The area under the plasma concentration-time curve (AUC) of PPC metabolites after oral intake of 12 mg racemic PPC was significantly lower in volunteers expressing the CYP2C92 or CYP2C93 allele. Increasing plasma AUC metabolic ratios (parent compound/metabolite) in CYP2C92 and CYP2C93 variant allele carriers were found for each hydroxylation reaction and the CYP2C93/3 genotype corresponded to an about 10-fold higher metabolic ratio of PPC (S)-7-hydroxylation relative to CYP2C91/*1. CYP2C9 polymorphisms cause a markedly compromised PPC (S)-7-hydroxylation. However, PPC metabolism appears overall less influenced by CYP2C9 genotype compared with other oral anticoagulants and it may thus be a valuable alternative for therapeutic anticoagulation of patients expressing CYP2C9 variant alleles.