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

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 CYP 3A是代谢许多心血管药物的主要酶系统，包括钙通道阻滞剂、CCB和他汀类药物。CYP 3A活性的显著个体间变异性导致药物反应可变，但也可能影响与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。 另一种重要的CYP 3A基因CYP 3A 5的多态性已被证明会导致个体间CYP 3A 5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，对维拉帕米的血压反应因CYP 3A 5基因型而异，尽管这些数据无法辨别这是否是由于该基因对维拉帕米的PK或药效学效应。 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，CYP 3A 5基因型对CYP 3A药物相互作用可变。 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。 这项研究应该提供深入了解CYP 3A 5基因型在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的作用。

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, CVdrugs, including calcium channel blockers, CCBs and statins. The substantial inter-individual variability of CYP3A activity 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. 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 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 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 effect of the gene on verapamil. We hypothesize CYP3A5 genotype contributes to variable responses to verapamil via both PK and PD and 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. These aims will be accomplished through a series of steady state PK studies of verapamil, atorvastatin and the combination in healthy volunteers. The research should provide insight into the role of CYP3A5 genotype in PK and drug interactions for two major cardiovascular drug classes metabolized by CYP3A.