Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans.
Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans.
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DOI：
10.1086/597125
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发表时间：
2009-03-15
期刊：
影响因子：
--
通讯作者：
Wilkinson GR
中科院分区：
文献类型：
--
作者：
Haas DW;Gebretsadik T;Mayo G;Menon UN;Acosta EP;Shintani A;Floyd M;Stein CM;Wilkinson GR
CYP 2B 6基因多态性影响奈韦拉平和依法韦仑的稳态血药浓度在许多资源有限的国家，单剂量奈韦拉平已被广泛用于孕妇分娩时，以减少母婴传播。我们描述了单剂量奈韦拉平和依法韦仑的遗传多态性与药代动力学之间的关系。非妊娠、HIV阴性的非裔美国人口服200 mg奈韦拉平后13天内测定血浆药物浓度。随后给予600 mg口服剂量的依法韦仑，并重复进行药代动力学采样。使用非房室方法估计药代动力学参数。主要分析涉及已知可预测稳态血浆奈韦拉平和依法韦仑暴露量增加的两种CYP 2B 6多态性（516 G>T和983 T>C）。探索性分析涉及CYP 2B 6、ABCB 1、CYP 3A 4和CYP 3A 5的另外51个多态性。基于复合CYP 2B 6 516/983基因型，34名参与者包括10个广泛型，17个中间型和7个慢代谢型。复合CYP 2B 6 516/983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。探索性分析表明，其他CYP 2B 6多态性与奈韦拉平和依法韦仑的药代动力学之间可能存在相关性。单次给药奈韦拉平后耐药HIV-1的选择压力可能因CYP 2B 6 516/983基因型而无实质性差异。其他多态性、基因和人群需要进一步研究。
Polymorphisms in CYP2B6 affect steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, single-dose nevirapine has been widely prescribed to pregnant women at delivery to reduce mother-to-child transmission. We characterized relationships between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz. Plasma drug concentrations were determined over 13 days following a 200-mg oral dose of nevirapine administered to non-pregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered and pharmacokinetic sampling repeated. Pharmacokinetic parameters were estimated using a non-compartmental approach. Primary analyses involved two 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. Based on composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. Composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not for nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and pharmacokinetics for nevirapine and efavirenz. Selective pressure for drug-resistant HIV-1 following single-dose nevirapine may not differ substantially by CYP2B6 516/983 genotype. Additional polymorphisms, genes and populations warrant further study.
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3
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