Haas David W, Gebretsadik Tebeb, Mayo Gail, Menon Usha N, Acosta Edward P, Shintani Ayumi, Floyd Michael, Stein C Michael, Wilkinson Grant R
USA.
J Infect Dis. 2009 Mar 15;199(6):872-80. doi: 10.1086/597125.
Polymorphisms in CYP2B6 affect the steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, a single dose of nevirapine has been widely prescribed to pregnant women at delivery, to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). We characterized associations between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz.
Plasma drug concentrations were determined over the 13-day period after administration of a 200-mg oral dose of nevirapine to nonpregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered, and pharmacokinetic sampling was repeated. Pharmacokinetic parameters were estimated using a noncompartmental approach. Primary analyses involved 2 CYP2B6 polymorphisms (516G --> T and 983T --> C) known to predict increased steady-state plasma nevirapine and efavirenz exposure. Exploratory analyses involved another 51 polymorphisms in CYP2B6, ABCB1, CYP3A4, and CYP3A5.
On the basis of the composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. The composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and the pharmacokinetics of nevirapine and efavirenz.
Selective pressure for drug-resistant HIV-1 after administration of single-dose nevirapine may not differ substantially according to CYP2B6 516/983 genotype. Additional polymorphisms, genes, and populations warrant further study.
细胞色素P450 2B6（CYP2B6）基因多态性会影响奈韦拉平和依非韦伦的稳态血药浓度。在许多资源有限的国家，分娩时给孕妇单次服用奈韦拉平已被广泛应用，以减少人类免疫缺陷病毒1型（HIV-1）的母婴传播。我们对基因多态性与单次服用奈韦拉平和依非韦伦的药代动力学之间的关联进行了特征分析。
对未怀孕、HIV阴性的非裔美国人单次口服200mg奈韦拉平后13天内的血浆药物浓度进行测定。随后给予600mg口服依非韦伦，并重复药代动力学采样。采用非房室方法估算药代动力学参数。主要分析涉及2种已知可预测奈韦拉平和依非韦伦稳态血药浓度升高的CYP2B6基因多态性（516G→T和983T→C）。探索性分析涉及CYP2B6、ATP结合盒转运蛋白B1（ABCB1）、细胞色素P450 3A4（CYP3A4）和细胞色素P450 3A5（CYP3A5）中的另外51种多态性。
基于CYP2B6 516/983复合基因型，34名参与者包括10名快代谢型、17名中间代谢型和7名慢代谢型基因型。CYP2B6 516/983复合基因型与依非韦伦的血浆药物暴露和清除率显著相关，但与奈韦拉平无关。探索性分析提示CYP2B6其他多态性与奈韦拉平和依非韦伦的药代动力学之间可能存在关联。
根据CYP2B6 516/983基因型，单次服用奈韦拉平后对耐药HIV-1的选择压力可能没有实质性差异。其他多态性、基因和人群值得进一步研究。
