CYP3A5 GENOTYPE: INFLUENCE ON PHARMACOKINETICS, PHARMACODYNAMICS, AND DRUG INTS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 CYP 3A是代谢许多心血管（CV）药物（包括钙通道阻滞剂（CCB）和他汀类药物）的主要酶系统。CYP 3A活性的个体间显著变异性不仅导致药物反应可变，还可能影响与CYP 3A抑制剂发生严重药物相互作用的风险。 对CYP 3A主要酶CYP 3A 4的遗传多态性的研究是相互矛盾的。 相反，另一个重要的CYP 3A，CYP 3A 5的多态性已被证明在个体之间引起CYP 3A 5的表达和活性的巨大差异。 这些多态性与某些CYP 3A底物的药代动力学（PK）差异相关，也与盐敏感性高血压相关。 主要研究者最近通过一项大型临床试验的数据显示，对维拉帕米的血压（BP）反应因CYP 3A 5基因型而异，尽管这些数据无法辨别这是由于基因对维拉帕米的PK或药效学（PD）效应。 因此，我们假设CYP 3A 5基因型通过PK和PD对维拉帕米的反应可变。 我们还假设CYP 3A 5基因型有助于变量CYP 3A药物相互作用。 我们将比较42例按CYP 3A 5基因型入组的受试者中维拉帕米的PK和PD。 我们还将通过检测维拉帕米-阿托伐他汀相互作用来评估CYP 3A 5基因型对CYP 3A药物相互作用的影响。 这些目标将通过在健康志愿者中进行的维拉帕米、阿托伐他汀和复方制剂的一系列稳态PK研究来实现。 拟议的研究应提供深入了解CYP 3A 5基因型的作用，在PK和药物相互作用的两个主要的心血管药物类代谢的CYP 3A。 这也将有助于了解CYP 3A 5遗传变异性在CCB药理作用中的作用。 这些信息可能会导致未来通过使用患者的遗传信息来改善这些心血管药物类别的治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CYP3A is a major enzyme system that metabolizes many cardiovascular (CV) drugs, including calcium channel blockers (CCBs) and statins. The substantial inter-individual variability of CYP3A activity not only contributes to variable drug responses, but also may influence the risk for serious drug interactions with CYP3A inhibitors. Studies of the genetic polymorphisms of CYP3A4, the major CYP3A enzyme, are conflicting. Conversely, polymorphisms of CYP3A5, the other important CYP3A, have been shown to cause great variability in expression and activity of CYP3A5 among individuals. These polymorphisms have been associated with differences in pharmacokinetics (PK) of some CYP3A substrates, and have also been associated with salt-sensitive hypertension. The principal investigator has recently shown through data from a large clinical trial that blood pressure (BP) responses to verapamil differ by CYP3A5 genotypes, although it is not possible with those data to discern whether this is due to a PK or pharmacodynamic (PD) effect of the gene on verapamil. Therefore, we hypothesize CYP3A5 genotype contributes to variable responses to verapamil via both PK and PD. We also hypothesize that CYP3A5 genotype contributes to variable CYP3A drug interactions. We will compare PK and PD of verapamil among 42 subjects enrolled by CYP3A5 genotypes. We will also assess the influence of CYP3A5 genotype on CYP3A drug interactions by testing the verapamil-atorvastatin interaction. These aims will be accomplished through a series of steady state PK studies of verapamil, atorvastatin and the combination in healthy volunteers. The proposed research should provide insight into the role of CYP3A5 genotype in PK and drug interactions for two major cardiovascular drug classes metabolized by CYP3A. It will also help understand the role of CYP3A5 genetic variability in the pharmacological effects of CCBs. Such information may lead to future improvements in therapy with these cardiovascular drug classes through use of patients' genetic information.