Exploration of CYP450 and Drug Transporter Genotypes and Correlations with Nevirapine Exposure in Malawians

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

KEYWORDS::

• CYP2B6
• CYP450
• Malawi
• nevirapine
• nuclear receptor
• P-glycoprotein
• pharmacokinetics

Financial & competing interests disclosure

This study was supported in part by the Pharmacogenetics for Every Nation Initiative, the Pharmacogenetics Research Network (NIH U01 GM63340), the UNC Translational and Clinical Sciences Institute (UL1RR025747), NIH Grant GM60346, Cancer Center Support Grant (NIH P30 CA21765), and by the American Lebanese Syrian Associated Charities (ALSAC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was supported in part by the Pharmacogenetics for Every Nation Initiative, the Pharmacogenetics Research Network (NIH U01 GM63340), the UNC Translational and Clinical Sciences Institute (UL1RR025747), NIH Grant GM60346, Cancer Center Support Grant (NIH P30 CA21765), and by the American Lebanese Syrian Associated Charities (ALSAC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.