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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞色素P3A是代谢多种心血管药物的主要酶系统，包括钙通道阻滞剂(CCBS)和他汀类药物。细胞色素P3A活性的个体间差异很大，不仅导致药物反应不同，还可能影响药物与细胞色素P3A抑制剂发生严重相互作用的风险。对于主要的细胞色素P3A酶--细胞色素P3A4的遗传多态的研究是相互矛盾的。与之相反，另一种重要的细胞色素P3A--细胞色素P3A5基因的多态也会导致细胞色素P3A5的表达和活性在个体间产生很大的差异。这些多态与某些CYP3A底物的药代动力学(PK)差异有关，也与盐敏感型高血压有关。首席研究人员最近通过一项大型临床试验的数据表明，血压(BP)对维拉帕米的反应因CYP3A5基因类型而异，尽管利用这些数据无法区分这是由于PK还是该基因对维拉帕米的药效学(PD)效应。因此，我们假设CYP3A5基因可能通过PK和PD参与维拉帕米的不同反应。我们还假设，CYP3A5基因对不同的CYP3A药物相互作用有贡献。我们将比较42例携带CYP3A5基因的受试者维拉帕米的PK和Pd。我们还将通过测试维拉帕米-阿托伐他汀的相互作用来评估CYP3A5基因对CYP3A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维拉帕米、阿托伐他汀及其组合的一系列稳态PK研究来实现。这项拟议的研究将为了解CYP3A代谢的两类主要心血管药物在PK和药物相互作用中的作用提供洞察力。这也将有助于理解CYP3A5的遗传变异性在CCBS的药理作用中的作用。这些信息可能会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.