Dataset Information

Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.

ABSTRACT: Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria.Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated.All CYP2C19/CYP2C9 alleles obeyed Hardy-Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC(0-24)) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C(max) (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071).CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.

SUBMITTER: Janha RE

PROVIDER: S-EPMC3870622 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.

Janha Ramatoulie E RE Sisay-Joof Fatoumatta F Hamid-Adiamoh Majidah M Worwui Archibald A Chapman Hannah L HL Opara Hyginus H Dunyo Sam S Milligan Paul P Rockett Kirk K Winstanley Peter P Pirmohamed Munir M Miller Ann K AK Conway David J DJ Walton Robert T RT

Pharmacogenomics 20090901 9

<h4>Aims</h4>Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria.<h4>Materials & methods</h4>Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated.<h4>Results</h4>All CYP ...[more]

PMID: 19761366

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Project description:Background Genetic diversity of cytochrome P450 2C subfamily metabolizing epoxyeicosatrienoic acids, vasoactive substances with a wide range of biological actions in the cardiovascular system, contributes to the molecular basis of coronary artery disease (CAD). Association between genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and CAD risk has been extensively investigated in Chinese, Japanese, Korean and other Asian populations whereas a few studies have been done in Europeans. The present study investigated whether common single nucleotide polymorphisms (SNPs) of CYP2C8, CYP2C9 and CYP2C19 genes are important risk factors of CAD in a Russian population. Methods DNA samples from 1,255 unrelated subjects comprising 561 patients with angiographically diagnosed CAD and 694 age- and sex-matched healthy subjects were genotyped for six SNPs such as rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. Results SNP rs4918758 of CYP2C9 was associated with decreased risk of CAD with odds ratio 0.61 adjusted for sex and age (codominant genetic model, 95% CI: 0.41–0.92, P=0.038, Q =0.20). Log-likelihood ratio test pointed out epistatic interactions between SNPs rs9332242 and rs61886769 of CYP2C9 at a codominant genetic model (Pinteraction =0.02). Moreover, SNP rs9332242 of CYP2C9 showed a trend towards association with increased CAD risk in cigarette smokers (P=0.049, Q =0.29). Bioinformatic analysis using the SNP prediction tool revealed a regulatory potential for all SNPs associated with CAD. Conclusions To our knowledge, the present study is the first to show that polymorphisms rs4918758 and rs9332242 of CYP2C9 represent significant genetic markers of CAD susceptibility in Europeans. A validation of genetic markers associated with CAD risk in different races and ethnicities may cut corners between discovery and clinical qualification of such markers for the purposes of translational medicine. The study was supported by the Russian Science Foundation.

Project description:ObjectivesThe aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B).MethodsStudy A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1-2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods.ResultsIn Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (Cmax; from 31.2 to 34.0 ng/mL) and elimination half-life (T½; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in Cmax versus the CYP2C9*1/*1 genotype. The mean T½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies.ConclusionsChanges in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans.

Dataset Information

Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.

Publications

Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.

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