Disparities in emergency contraceptive metabolism dictate efficacy

总结 拟议的项目旨在增加我们对药物基因组学交叉点的了解， 避孕效果和健康差距。美国有色人种女性面临更大的风险 避孕失败，导致比白色同龄人更多的意外怀孕。而社会 健康的决定因素，如种族歧视和获得医疗保健的机会， 避孕的可用性和使用，固有的药物基因组学差异也可以解释显着 个体与个体之间的功效差异。最有效的口服紧急避孕药（EC）方法， 醋酸乌利司他（UPA）通过阻断排卵前卵泡中的孕酮作用而起作用， 即使在最佳剂量下，在某些人群中也不太有效。我们已经证明了UPA被转化为 通过酶细胞色素P450 3A 5（CYP 3A 5）转化为无活性代谢物。此外，我们确定， 灵长类动物的卵巢卵泡，UPA作为EC的作用部位，表达显著高水平的CYP 3A 5， 围排卵期和黄体发育。活性变异的基因型和表型频率 CYP 3A 5在黑人中显著高于白人，后者 主要具有非功能性变体。因为活性CYP 3A 5是药物的主要贡献者， 因此，我们假设UPA在阻止患有高脂血症的女性排卵方面的效果明显较差。 活性CYP 3A 5变体。在这个建议中，我们将确定卵泡CYP 3A 5是否降低卵巢内UPA水平 相对于使用临床相关的恒河猴模型全身观察到的（目的1）。研究 还将进行测定，以确定阻断CYP 3A 5活性是否导致UPA在抑制 排卵所必需的过程。在补充的人类受试者研究中，我们计划评估CYP 3A 5 基因型（活性与非活性形式）决定UPA的功效（目的2）。本研究招募的女性将 基因分型并分类为具有活性或非活性CYP 3A 5等位基因，然后评估UPA 药效学我们还将探索可能在药物代谢中发挥作用的其他遗传变异。的 主要终点包括确定UPA未能预防的比率是否存在显著差异。 排卵和UPA代谢的药代动力学与CYP 3A 5基因型有关。的结果 研究将确定在避孕效果方面是否存在种族差异的遗传倾向， 意外怀孕的风险。这项研究的广泛的长期目标包括提供一种手段， 通过测试确定有失败风险的个体，最大限度地发挥UPA在女性中的治疗潜力 和/或开发限制药物代谢的方法。

SUMMARY The proposed project aims to increase our knowledge regarding the intersection of pharmacogenomics, contraceptive efficacy, and health disparities. U.S. women of color are at much greater risk of experiencing contraceptive failure, resulting in more unintended pregnancies than their white peers. While social determinants of health, such as racial discrimination and access to healthcare, contribute meaningfully to contraceptive availability and use, inherent pharmacogenomic differences could also account for significant individual-to-individual disparities in efficacy. The most effective oral emergency contraceptive (EC) method, ulipristal acetate (UPA), which works by blocking progesterone action in the preovulatory follicle, appears to be less effective in certain populations even when optimally dosed. We have demonstrated that UPA is converted to inactive metabolites by the enzyme cytochrome P450 3A5 (CYP3A5). Moreover, we established that the primate ovarian follicle, the site of UPA action as an EC, expresses remarkably high levels of CYP3A5 through the periovulatory interval and luteal development. The genotype and phenotype frequency of an active variant of CYP3A5 is significantly greater in those identifying as Black as compared to whites, with the latter possessing primarily a nonfunctional variant. Because active CYP3A5 is a major contributor to drug metabolism, we hypothesize that UPA is significantly less effective at preventing ovulation in women 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 rhesus macaque 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 human subjects studies, we plan to assess if CYP3A5 genotype (active versus inactive form) determines UPA efficacy (Aim 2). Women 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. The results of the studies will determine if a genetic predisposition exists for racial disparities in contraceptive efficacy and the risk for unintended pregnancy. The broad, long-term goal of this research includes providing a means to maximize the therapeutic potential of UPA in women through testing to identify individuals at risk for failure and/or developing approaches to limit drug metabolism.