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

CYP3A5 基因型：对药代动力学、药效学和药物结构的影响

• 批准号: 7605484
• 负责人: Julie E. Johnson
• 金额: $ 9.86万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-23 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605484
• 关键词: Blood Pressure; CYP3A4 gene; CYP3A5 gene; Calcium Channel Blockers; Cardiovascular Agents; Class; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Conflict (Psychology); Data; Drug Interactions; Drug Kinetics; Enrollment; Enzymes; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Grant; Hypertension; Individual; Institution; Lead; Patients; Pharmaceutical Preparations; Pharmacodynamics; Principal Investigator; Research; Research Personnel; Resources; Risk; Role; Series; Source; System; Testing; United States National Institutes of Health; Verapamil; atorvastatin; cytochrome P450 3A; healthy volunteer; inhibitor/antagonist; insight; response; salt sensitive

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 CYP3A是一种主要的酶系统，可以代谢许多心血管（CV）药物，包括钙通道阻滞剂（CCB）和他汀类药物。 CYP3A活性的实质间个体差异不仅有助于可变的药物反应，而且可能影响与CYP3A抑制剂严重相互作用的风险。 CYP3A4（主要CYP3A酶）的遗传多态性的研究是矛盾的。 相反，其他重要的CYP3A的CYP3A5的多态性已被证明会在个体中引起CYP3A5的表达和活性差异。 这些多态性与某些CYP3A底物的药代动力学（PK）差异有关，并且也与盐敏感高血压有关。 主要研究者最近通过大型临床试验的数据表明，血压（BP）对Verapamil的血压反应因CYP3A5基因型而有所不同，尽管这些数据不可能识别这是否是由于PK还是药物学（PD）对Verapamil的效应。 因此，我们假设CYP3A5基因型通过PK和PD促进了对Verapamil的可变响应。 我们还假设CYP3A5基因型有助于可变的CYP3A药物相互作用。 我们将比较Verapamil的PK和PD与CYP3A5基因型招募的42名受试者。 我们还将通过测试Verapamil-Atorvastatin相互作用来评估CYP3A5基因型对CYP3A药物相互作用的影响。 这些目标将通过一系列的维拉帕米，阿托伐他汀和健康志愿者的组合来实现。 拟议的研究应洞悉CYP3A5基因型在PK和药物相互作用中的作用，以及两种由CYP3A代谢的主要心血管药物类别的药物相互作用。 它还将有助于了解CYP3A5遗传变异性在CCB的药理作用中的作用。 通过使用患者的遗传信息，这些信息可能会导致这些心血管药物类别的治疗未来改善。