Establishment of The Effective and Safe Anticoagulation Therapy for Japanese Patients

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To investigate the population differences in the metabolic activity of cytochrome P450 (CYP) 2C9 between genotypically-matched Caucasians and Japanese using the unbound oral clearance (CLpo,u) of (S)-warfarin as an in vivo probe.Ninety Japanese and 47 Caucasian patients on maintenance warfarin therapy were studied. Steady-state plasma unbound concentrations (Cu) of (S)-warfarin were measured by a chiral HPLC method coupled with ultrafiltration techniques. CLpo,u for (S)-warfarin and the formation clearance (CLm) of (S)-7-hydroxywarfarin were determined. Genotyping of CYP2C9 was performed with a polymerase chain reaction method for 6 distinct alleles (CYP2C9^*1, CYP2C9^*2, CYP2C9^*3, CYP2C9^*4, CYP2C9^*5 and a T/C transition in intron 2).The frequency distribution of CLpo,u for (S)-warfarin obtained from Japanese was shifted towards higher values as compared to that in Caucasians. Japanese had lower allelic frequencies for the 5 variants than Caucasians. When inter-population comparison … More s of CYP2C9 activity were made for genotype-matched subjects, Japanese with the homozygous CYP2C9^*1 (wild-type) genotype (n = 85) had significantly (p<0.01) greater median values for CLpo,u and CLm than the Caucasians with the corresponding genotype (n = 26) : 10.4 vs 4.25 ml/min/kg and 0.015 vs 0.010 ml/min/kg, respectively. In addition, heterozygous Japanese for the CYP2C9^*3 genotype (n = 4) showed a significantly (p<0.05) reduced CLpo,u for (S)-warfarin by 63 % as compared with Japanese possessing the homozygous CYP2C9^*1 genotype. By contrast, no significant differences were observed in this parameter among the Caucasian with the homozygous CYP2C9^*1 genotype and those with heterozygous CYP2C9^*2 or CYP2C9^*3 genotypes.These findings indicate that inter-population differences in the frequencies of known variant CYP2C9 alleles account only in part for the variability observed in in vivo CYP2C9 activity in different populations. Additionally, a gene-dose effect of defective CYP2C9 alleles on the in vivo CYP2C9 activity is evident in Japanese but not in Caucasians. Further studies are required to identify concealed factor(s) (e.g., transcriptional regulation) responsible for the large intra- and inter-population variability in CYP2C9 activity. Less