METABOLISM OF WARFARIN ENANTIOMERS IN JAPANESE PATIENTS WITH HEART-DISEASE HAVING DIFFERENT CYP2C9 AND CYP2C19 GENOTYPES

Objective: To determine whether genetic polymorphism of cytochrome P45 0 (CYP) 2C9 or 2C19 affects the in vivo metabolism of warfarin enantio mers. Methods: Eighty-six Japanese patients heart disease who were giv en warfarin participated in the study. Plasma unbound concentrations o f warfarin enantiomers and urinary (S)-7-hydroxywarfarin concentration s were measured by means of a chiral HPLC and ultrafiltration techniqu e to calculate the unbound oral clearance (CLpo,u) for the enantiomers and the formation clearance (CLm) for (S)-warfarin 7-hydroxylation, G enotyping for CYP2C9 (the wild type [wt], Arg(144)/Cys, and Ile(359)/L eu) and for CYP2C19 (wt, m1, and m2) was performed with a polymerase c hain reaction method. Results: Three patients were heterozygous for th e CYP2C9 Leu(359) mutation but none were homozygous for the mutation ( the allele frequency of 0.017). None had a CYP2CP Cys(144) allele. The medians for (S)-warfarin CLpo,u and its 7-hydroxylation CLm obtained from heterozygotes of CYP2C9 Leu(359) were significantly less than tho se obtained from homozygotes of the wt allele, as follows: 234 ml/min (range, 156 to 269 ml/min) versus 632 ml/min (range, 180 to 2070 ml/mi n) (p < 0.001) and 0.20 ml/min (range, 0.05 to 0.77 ml/min) versus 0.8 0 ml/min (range, 0.05 to 14.9 ml/min) (p < 0.05), respectively. In con trast, no difference was observed in (R)-warfarin CLpo,u between the g roups. The allele frequencies for CYP2C19(m1) and CYP2C19(m2) were 0.2 6 and 0.14, respectively, indicating 15% of patients were genotypicall y poor metabolizers of CYP2C19. No difference in CLpo,u for warfarin e nantiomers was observed between the assumed CYP2C19 phenotypes, Conclu sion: Heterozygotes for CYP2C9 Ile(359)/Leu allele have reduced in viv o metabolism of (S)-warfarin but not (R)-warfarin. Because (S)-warfari n has a greater anticoagulant potency than its (R)-congener, the genet ic polymorphism of CYP2C9 may partly account for the large interpatien t variability in therapeutic dosages of warfarin.