Disparities in emergency contraceptive metabolism dictate efficacy

摘要 拟议的项目旨在增加我们关于药物基因组学交叉的知识， 避孕药效和健康差距。美国有色人种女性患癌症的风险要大得多 避孕失败，导致比白人同龄人更多的意外怀孕。在社交方面 决定健康的因素，如种族歧视和获得医疗保健的机会，对 避孕措施的可获得性和使用，固有的药物基因组差异也可能解释显著 个体之间在疗效上的差异。最有效的口服紧急避孕(EC)方法， 醋酸利普列酯(UPA)通过阻断排卵前卵泡中的黄体酮作用，似乎是 在某些人群中效果较差，即使在最佳剂量下也是如此。我们已经证明了uPA是由 通过细胞色素P450 3A5(CYP3A5)酶将代谢产物失活。此外，我们还确定， 灵长类卵泡是uPA作为EC的作用部位，通过 排卵间期与黄体发育。活性变异体的基因型别和表型频率 与白人相比，那些认为自己是黑人的人的CYP3A5明显更大，后者 主要具有非功能性变体的。因为活性的CYP3A5是药物的主要贡献者 新陈代谢方面，我们假设uPA在预防妇女排卵方面的效果显著降低。 活性细胞色素P3A5变异体。在这项建议中，我们将确定卵泡细胞色素P3A5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系统观察到的(目标1)。研究 也将进行研究，以确定阻断CYP3A5活性是否会导致更强的uPA抑制效果 排卵所必需的过程。在互补的人类受试者研究中，我们计划评估CYP3A5 基因(活性与非活性)决定了uPA的疗效(目标2)。这项研究招募的女性将是 对具有活性或非活性的CYP3A5等位基因进行基因分型和分类，然后评估uPA 药效学。我们还将探索其他可能在药物新陈代谢中发挥作用的遗传变异。这个 主要终点包括确定uPA未能阻止的比率是否存在显著差异 排卵和尿激酶型纤溶酶原激活剂代谢的药代动力学与CYP3A5基因相关。评选结果 研究将确定是否存在避孕效果种族差异的遗传倾向，以及 意外怀孕的风险。这项研究的广泛、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.