Functional impact of CYP2C*5, CYP2C9*6, CYP2C9*8, and CYP2C9*11 in vivo among black Africans

Background and Aim: Previous data indicate that the urinary losartan/E-3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo. The functional impact of CYP2C9(star)5, (star)6, (star)8, and (star)11 polymorphisms in vivo has not been investigated previously in humans. Methods: A single oral dose of losartan (25 mg) was given to 19 Beninese subjects with CYP2C9(star)1/(star)1 (n = 9), (star)1/(star)5 (n = 1), (star)1/(star)6 (n = 1), (star)1/(star)8 (n = 2), (star)1/(star)11 (n = 3), (star)5/(star)6 (n = 1), (star)5/(star)8 (n = 1), and (star)8/(star)11 (n = 1) genotypes. Concentrations of losartan and its active metabolite E-3174 were determined in urine from 0 to 8 hours by HPLC. The losartan/E-3174 metabolic ratio was used as a measure of losartan oxidation in vivo. Results: The urinary losartan/E-3174 ratio in the various genotypes was as follows: 1.85 +/- 2.4 (mean +/- SD) for CYP2C9(star)1/(star)1, 14.6 for CYP2C9(star)1/star5, 4.2 for CYP2C9(star)1/(star)6, 188 for CYP2C9(star)5/(star)6, 11.6 for CYP2C9(star)5/(star)8, 0.44 +/- 0.13 (mean +/- SD) for CYP2C9(star)1/(star)8, 2.2 for CYP2C9(star)8/(star)11, and 5.72 +/- 4.5 (mean +/- SD) for CYP2C9(star)1/(star)11. Compared with the CYP2C9(star)1/(star)1 genotypes, the losartan/E-3174 ratio was significantly different in the CYP2C9(star)5 allele carriers (CYP2C9(star)1/(star)5, CYP2C9(star)5/(star)8, and CYP2C9(star)5/(star)6 genotypes) (P = .01, Mann-Whitney) but was not different in CYP2C9(star)1/(star)8 (P = .16) and CYP2C9(star)1/(star)11 (P = .11) carriers. The urinary losartan/E-3174 ratio of the single CYP2C9(star)1/(star)6 subject was higher than the 95% confidence interval of the mean of the CYP2C9(star)1/(star)1 group (0.0-3.7), whereas the metabolic ratio of the CYP2C9(star)8/(star)11 carrier was inside the 95% confidence interval of the means of the CYP2C9(star)1/(star)1 and CYP2C9(star)1/(star)11 groups (0.0-18). Conclusions: The CYP2C9(star)5 and (star)6 alleles are associated with decreased enzyme activity in vivo compared with the wild-type variant, whereas the CYP2C9(star)8 and (star)11 variants did not appear to have large in vivo effects.