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Functional impact of CϒP2C9*5 , CϒP2C9*6 , CϒP2C9*8 , and CϒP2C9*11 in vivo among black Africans
Author(s) -
Allabi Aurel C.,
Gala JeanLuc,
Horsmans Yves,
Babaoglu Melih Onder,
Bozkurt Atila,
Heusterspreute Michel,
Yasar Umit
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.04.001
Subject(s) - cyp2c9 , losartan , in vivo , chemistry , genotype , endocrinology , metabolite , medicine , urine , pharmacology , cytochrome p450 , biology , biochemistry , angiotensin ii , metabolism , genetics , receptor , gene
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*5 , *6 , *8 , and *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*1/*1 (n = 9), *1/*5 (n = 1), *1/*6 (n = 1), *1/*8 (n = 2), *1/*11 (n = 3), *5/*6 (n = 1), *5/*8 (n = 1), and *8/*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*1/*1 , 14.6 for CYP2C9*1/*5 , 4.2 for CYP2C9*1/*6 , 188 for CYP2C9*5/*6 , 11.6 for CYP2C9*5/*8 , 0.44 ± 0.13 (mean ± SD) for CYP2C9*1/*8 , 2.2 for CYP2C9*8/*11 , and 5.72 ± 4.5 (mean ± SD) for CYP2C9*1/*11 . Compared with the CYP2C9*1/*1 genotypes, the losartan/E‐3174 ratio was significantly different in the CYP2C9*5 allele carriers ( CYP2C9*1/*5 , CYP2C9*5/*8 , and CYP2C9*5/*6 genotypes) ( P = .01, Mann‐Whitney) but was not different in CYP2C9*1/*8 ( P = .16) and CYP2C9*1/*11 ( P = .11) carriers. The urinary losartan/E‐3174 ratio of the single CYP2C9*1/*6 subject was higher than the 95% confidence interval of the mean of the CYP2C9*1/*1 group (0.0–3.7), whereas the metabolic ratio of the CYP2C9*8/*11 carrier was inside the 95% confidence interval of the means of the CYP2C9*1/*1 and CYP2C9*1/*11 groups (0.0–18). Conclusions The CYP2C9*5 and *6 alleles are associated with decreased enzyme activity in vivo compared with the wild‐type variant, whereas the CYP2C9*8 and *11 variants did not appear to have large in vivo effects. Clinical Pharmacology & Therapeutics (2004) 76 , 113–118; doi: 10.1016/j.clpt.2004.04.001