Impact of Pregnancy on Drug Absorption, Disposition and End Organ Response

描述(由申请人提供)：这份提案描述了匹兹堡大学的产科-胎儿药理学研究单位(OPRU)。匹兹堡OPRU在其最初目标方面取得了巨大成功，并为OPRU网络作出了重大贡献。我们参与了概念提案、方案制定、征聘、数据分析和数据共享。匹兹堡OPRU将其研究重点放在17-羟孕酮己酸酯的研究上，17-羟孕酮己酸酯是目前唯一被证明可以降低早产妇女早产风险的药物。我们已经定义了这种药物的药理学，并代表OPRU在全国会议上提交了我们的数据。在这项应用中，我们建议研究用于短子宫颈孕妇的阴道孕酮的药理学。美国妇产科学会最近的一次呼吁鼓励研究，以确定孕酮在怀孕期间使用的适当剂量和配方。我们将招募怀孕16至22周的妇女，其宫颈长度为30毫米。这些妇女早产的风险很高。我们将在治疗前获取宫颈阴道液，并在使用两种孕激素之一(Prochieve和Prometrium)治疗后每周再次获取宫颈阴道液，具有明显的临床益处。我们将评估这两种药物的药代动力学(PK)以及这些药物对宫颈阴道液生物标记物的药效学影响，包括宫颈长度和密度、基质金属蛋白酶、细胞因子和宫颈阴道蛋白质组。这些分析将使我们能够比较这两种孕激素的PK，确定它们的靶点，并评估这些治疗是否会改变宫颈结构。我们的第二项研究将评估药物代谢酶和妊娠激素的多态性对两种主要药物代谢酶2C9和2D6活性的影响。我们将对200名孕妇进行筛查，并确定那些P450酶基因多态性已知会影响酶活性的人。这些多态通常会导致酶活性的高度变化。我们将给这些妇女服用由吲哚美辛和右美沙芬组成的鸡尾酒，以评估细胞色素P450酶的活性，一次在怀孕期间，一次在产后。我们将获得在CYP、2C9和2D6中也表达感兴趣的多态的肝细胞，并用雌激素和孕激素来挑战它们，以确定激素的作用。最后，我们将通过评估脐带/胎盘CYP酶/多态来评估胎儿对这三种CYP酶活性变化的贡献。

DESCRIPTION (provided by applicant): This proposal describes the Obstetrical-Fetal Pharmacology Research Unit (OPRU) at the University of Pittsburgh. The Pittsburgh OPRU has been highly successful in its original objectives and has contributed to the Network of OPRUs substantially. We have participated in concept proposals, protocol development, recruitment, data analysis and data sharing. The Pittsburgh OPRU has focused its research on the study of 17-hydroxyprogesterone caproate, the only agent at the time shown to reduce the risk of preterm birth in women with a prior preterm birth. We have defined the pharmacology of this agent and have presented our data at national meetings on behalf of the OPRU. In this application, we propose to study the pharmacology of vaginal progestins used in pregnant women with a short cervix. A recent call from the American College of Obstetrics and Gynecology encouraged research to define the proper dosing and formulation for progestin use in pregnancy. We will recruit women between 16 and 22 weeks gestation whose cervix is < 30 mm in length. These women are at high risk for preterm birth. We will obtain cervicovaginal fluid prior to treatment and again weekly for 4 weeks after treatment with one of the two progestational agents (Prochieve and Prometrium) with apparent clinical benefit. We will evaluate the pharmacokinetics (PK) of these two agents as well as the pharmacodynamic impact of these agents on cervicovaginal fluid biomarkers including cervical length and density, matrix metalloproteinases, cytokines, and the cervicovaginal proteome. These analyses will allow us to compare the PK of these two progestins, identify their targets and evaluate whether these treatments alter cervical structure. Our second study will evaluate the impact of polymorphisms of drug metabolizing enzymes and pregnancy hormones on the activity of the two major drug metabolizing enzymes CYP, 2C9 and 2D6. We will screen 200 pregnant women and identify those with P450 enzyme polymorphisms known to affect enzyme activity. These polymorphisms commonly lead to a highly variable in enzyme activity. We will administer to these women a cocktail composed of indomethacin and dextromethorphan to evaluate the activity of the cytochrome P450 enzymes once during pregnancy and once postpartum. We will obtain hepatocytes which also express the polymorphisms of interest in CYP, 2C9 and 2D6 and challenge them with estrogen and progesterone to determine the hormone's effects. Finally, we will evaluate the fetal contribution to the variability in activity of these three CYP enzymes by evaluating cord/placental CYP enzymes/polymorphisms.