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.
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