Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans.

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Allabi AC, Gala JL, Horsmans Y, Babaoglu MO, Bozkurt A, Heusterspreute M, Yasar U

Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans.

Clin Pharmacol Ther. 2004 Aug;76(2):113-8.

PubMed ID

15289788 [ View in PubMed

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Abstract

UNLABELLED: 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.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Phenytoin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Celecoxib	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Warfarin	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Clopidogrel	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions	Details
Acetylsalicylic acid	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Glipizide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Tolbutamide	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, lower dose requirements	Details
Acenocoumarol	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	Effect Inferred	Poor drug metabolizer, associated with lower dose requirement.	Details
Phenprocoumon	Cytochrome P450 2C9 Gene symbol: CYP2C9 UniProt: P11712	CYP2C9*5	Not Available	1080C>G (rs28371686)	ADR Inferred	Associated with delayed stabilization. If carrier of rs9934438 as well, increased risk of severe overanticoagulation.	Details