Exploration of CYP450 and drug transporter genotypes and correlations with nevirapine exposure in Malawians. (January 2012)

• Record Type: Journal Article
• Authors: Brown, Kevin C; Hosseinipour, Mina C; Hoskins, Janelle M; Thirumaran, Ranjit K; Tien, Hsiao-Chuan; Weigel, Ralf; Tauzie, Jean; Shumba, Ida; Lamba, Jatinder K; Schuetz, Erin G; McLeod, Howard L; Kashuba, Angela DM; Corbett, Amanda H
• Is Part Of: Pharmacogenomics. Volume 13:Number 1(2012)
• Page Start: 113
• Page End: 121
• Publication Date: 2012-01
• Subjects: CYP2B6 -- CYP450 -- Malawi -- nevirapine -- nuclear receptor -- P-glycoprotein -- pharmacokinetics; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.11.132
• Languages: English
• ISSNs: 1462-2416

Abstract

Aim: Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians.Materials & methods: CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects.Results: Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27–2.40) for area under the concentration time curve (AUC)0–12 h, 1.58 (1.03–2.42) for C0, and 0.53 (0.31–0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027).Conclusion: Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure. Original submitted 15 June 2010; Revision submitted 5 July 2011