Pharmacogenomics of an ovulation modulator and the impact on delay of ovulation

SUMMARY The proposed project aims to increase our knowledge regarding the intersection of pharmacogenomics and drug therapeutics. A commonly used ovulation modulator, ulipristal acetate (UPA), works by blocking progesterone action in the preovulatory follicle and is metabolized through the cytochrome P450 pathway. We have demonstrated that UPA is converted to inactive metabolites by the enzyme cytochrome P450 3A5 (CYP3A5). Moreover, we established that the NHP ovarian follicle, the site of UPA action as an EC, expresses remarkably high levels of CYP3A5 through the periovulatory interval and luteal development which may further impact the therapeutic effect of this drug. Because active CYP3A5 is a major contributor to drug metabolism, we hypothesize that UPA is significantly less effective at preventing ovulation in those with the active CYP3A5 variant. In this proposal, we will determine if follicular CYP3A5 reduces intraovarian UPA levels relative to what is observed systemically (Aim 1) using the clinically relevant NHP model. Studies will also be performed to determine if blocking CYP3A5 activity leads to greater UPA efficacy in inhibiting processes essential for ovulation. In complementary clinical studies, we plan to assess if CYP3A5 genotype (active versus inactive form) determines UPA efficacy (Aim 2). Participants recruited for this study will be genotyped and categorized as possessing active or inactive CYP3A5 alleles and then assessed for UPA pharmacodynamics. We will also explore other genetic variants that might play a role in drug metabolism. The primary endpoint includes determining if significant differences exist in the rate at which UPA fails to prevent ovulation and the pharmacokinetics of UPA metabolism related to the CYP3A5 genotype. A long-term goal of this research includes providing a means to maximize the therapeutic potential of UPA through testing to identify individuals at risk for failure and/or developing approaches to limit drug metabolism as this class of drugs have the potential to be used widely for other therapeutic indications.