Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes

Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

“…12,13 To our surprise, we observed no significant difference in CL po,u for (S)-warfarin between the Caucasian patients with the homozygous wild-type CYP2C9 genotype and those with the heterozygous CYP2C9*2 or CYP2C9*3 genotype. Nonetheless, a patient having a combined heterozygote of CYP2C9*2 and CYP2C9*3 (ie, CYP2C9*2/*3) had CL po,u for (S)-warfarin that was 70% lower than the mean value for those with the homozygous wild-type CYP2C9 genotype.…”

“…27,31 Asians As none of the Asians so far studied were carriers of the CYP2C9*2 variant, it is impossible to assess the impact of this variant on the dose requirement of warfarin in Asians. While most of the previous studies [10][11][12][13][14][15][22][23][24][25][26][27][28][29][30][31] agreed that the patients possessing at least one CYP2C9*3 variant would require a significantly lower maintenance dose of warfarin than those possessing the homozygous wild-type genotype (CYP2C9*1/*1) irrespective of their ethnic backgrounds, there is a discernible difference in the impact of CYP2C9*3 variant on the warfarin doses between the populations. While Japanese patients with the CYP2C9*1/ *3 and CYP2C9*3/*3 genotypes have 50 and 90% lower warfarin doses than those with the CYP2C9*1/*1 genotype, respectively, 12-14 the impact of CYP2C9*3 on the warfarin dose appeared somewhat attenuated in Caucasians.…”

“…The Caucasian patients with the CYP2C9*1/*3 and CYP2C9*3/*3 genotypes have 20-45% and 75% lower warfarin doses than those with homozygous wild-type CYP2C9 genotype, respectively. 15,[24][25][26][27][28][29][30][31] Anecdotal observations indicated that the maintenance doses of warfarin obtained from Asians (ie, 3.4 and 3.3 mg/day for Japanese [12][13][14] and Chinese, 32 respectively) are 20-50% lower than those obtained from Caucasian (ie, 4.1-6.7 mg/day). 10,11,[22][23][24][25][26][27][28][29][30][31] We will discuss whether or not the assumed population difference in the maintenance dose of warfarin between Caucasians and Asians can be explained by the population difference in the polymorphisms of CYP2C9 in the separate chapter.…”

“…[10][11][12][13][14][15] We were the first to report that Japanese patients with the heterozygous and homozygous CYP2C9*3 allele exhibited a 63 and 89%, reduced unbound oral clearance (CL po,u ) for (S)-warfarin, respectively, as compared with those with the homozygous wild-type CYP2C9 allele. 12,13 As a significant gene-dose effect in CL po,u for (S)-warfarin by CYP2C9*3 variant was observed, we considered that the CYP2C9*3 variant may have a clinically significant impact on the anticoagulation response to warfarin even in a heterozygous genotype in Japanese patients.…”

“…Among the 11 variant alleles of CYP2C9 so far reported, 7 CYP2C9*2 and CYP2C9*3 would be most important in the light of their influence on in vitro and in vivo metabolic activities and allelic frequencies in different ethnic populations. [8][9][10][11][12][13][14][15] CYP2C9*4 16 has been detected so far in only one Japanese patient whose phenytoin clearance was shown to be substantially reduced as compared with those possessing CYP2C9*1/*1. The allelic frequency of this variant should be very low in Japanese and no information is available in Caucasian and African-American populations.…”