CYP2B6 genetic variations and drug interactions

描述（由申请人提供）：由于患者间对药物的反应存在较大差异，合理的药物治疗变得困难，药物清除率和药物相互作用的遗传差异也导致了这一点。本研究旨在通过对细胞色素P450（CYP）2B 6的研究，加深对基于遗传学和药物相互作用的可变药物反应机制的理解。CYP 2B 6是一种比其他CYP研究较少的酶，但在许多临床重要药物的代谢和随之而来的药物相互作用中起着核心作用。我们假设CYP 2B 6基因变异不仅影响许多药物的清除率和反应，而且影响药物相互作用过程中CYP 2B 6的相对易感性。PI实验室的研究已经确定了CYP 2B 6活性的特异性探针（依法韦仑）和定义tagSNP（G516 T和A785 G）的最常见和功能重要的变体等位基因（CYP 2B 6 *6）。本提案概述了体外和临床研究，以检测CYP 2B 6 *6等位基因对依法韦仑代谢和药物相互作用的影响。在目标一中，我们将检验CYP 2B 6 *6等位基因影响基线CYP 2B 6活性并改变体外抑制反应的假设。将在CYP 2B 6 *6等位基因分型的人肝脏微粒体中测定依法韦仑代谢和对抑制剂的敏感性。在目标二中，我们将通过测定依法韦仑（100 mg单次口服给药）的代谢来检验CYP 2B 6 *6等位基因影响体内CYP 2B 6活性的假设。在目标三中，我们将检验CYP 2B 6 *6等位基因影响体内抑制性药物相互作用的反应性的假设。将在CYP 2B 6 *6等位基因基因分型的健康志愿者中确定伏立康唑（PI新确定的抑制剂）对依法韦仑（100 mg单次给药）药代动力学的影响。在目标四，我们将测试的假设，CYP 2B 6 *6等位基因影响稳态暴露的药物进行“自诱导”的代谢，从而与他们相关的药物相互作用。1)将在CYP 2B 6 *6等位基因基因分型的健康志愿者中测定依法韦仑的单次和多次给药药代动力学; 2）将在依法韦仑多次给药之前和之后评估选定CYP的活性。总之，这些研究将为改善治疗奠定基础，通过优化有益作用和避免药物不良反应，使越来越多的药物通过CYP 2B 6代谢。

DESCRIPTION (provided by applicant): Rational drug therapy is made difficult by large interpatient variability in response to drugs, and inherited differences in drug clearance and drug interactions contribute to this. This proposal is directed at improving our understanding of mechanisms of variable drug response based on genetics and drug interactions through the study of cytochrome P450 (CYP) 2B6. CYP2B6 is an enzyme that has been studied less than other CYPs, but one that plays a central role in the metabolism of many clinically important drugs and the drug interactions that ensue. We hypothesize that CYP2B6 genetic variations influence not only the clearance of and response to many drugs but also the relative susceptibility of CYP2B6 during drug-drug interactions. Studies in the PI's laboratory have identified a specific probe of CYP2B6 activity (efavirenz) and the most common and functionally important variant allele (CYP2B6*6) defining tagSNPs (G516T and A785G). In vitro and clinical studies are outlined in this proposal to test the influence of CYP2B6*6 allele on efavirenz metabolism and drug interactions. In aim one, we will test the hypothesis that the CYP2B6*6 allele influences baseline CYP2B6 activity and alters response to inhibition in vitro. Efavirenz metabolism and susceptibility to inhibitors will be determined in microsomes from human livers genotyped for the CYP2B6*6 allele. In aim two, we will test the hypothesis that the CYP2B6*6 allele influences CYP2B6 activity in vivo by measuring the metabolism of efavirenz (100 mg single oral dose). In aim three, we will test the hypothesis that the CYP2B6*6 allele influences responsiveness to inhibitory drug interactions in vivo. The effect of voriconazole (a newly identified inhibitor by the PI) on efavirenz (100 mg single dose) pharmacokinetics will be determined in healthy volunteers genotyped for the CYP2B6*6 allele. In aim four, we will test the hypothesis that the CYP2B6*6 allele influences steady-state exposure of drugs that undergo "autoinduction" of their metabolism, and thereby the drug interactions associated with them. 1) Single- and multiple- dose pharmacokinetics of efavirenz will be determined in healthy volunteers genotyped for the CYP2B6*6 allele; 2) the activity of selected CYPs will be assessed before and after multiple doses of efavirenz. Together, these studies will lay the groundwork for improved therapy with a growing list of drugs that are metabolized by CYP2B6 through optimizing beneficial effects and avoiding adverse drug reactions.