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

描述（由申请人提供）：本提案描述了匹兹堡大学的产科胎儿药理学研究单位（OPRU）。匹兹堡外地方案研研所在实现其最初目标方面非常成功，并对外地方案研研所网络作出了重大贡献。我们参与了概念提案、协议制定、招聘、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，这是当时唯一一种被证明可以降低有早产史妇女早产风险的药物。我们已经确定了该药物的药理学，并代表OPRU在全国会议上展示了我们的数据。在这个应用中，我们建议研究阴道孕激素用于短宫颈孕妇的药理学。美国妇产科学院最近呼吁，鼓励研究确定妊娠期间使用黄体酮的适当剂量和配方。我们将招募宫颈长度小于30毫米的妊娠16 - 22周的妇女。这些妇女早产的风险很高。我们将在治疗前获得宫颈阴道液，并在使用两种孕药（Prochieve和Prometrium）中的一种治疗后每周获得一次，持续4周，临床效果明显。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志物的药效学影响，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黄体酮的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多态性对两种主要药物代谢酶CYP、2C9和2D6活性的影响。我们将筛选200名孕妇，并确定那些已知影响酶活性的P450酶多态性。这些多态性通常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，以评估怀孕期间和产后细胞色素P450酶的活性。我们将获得同样表达CYP、2C9和2D6基因多态性的肝细胞，并用雌激素和黄体酮刺激它们，以确定激素的作用。最后，我们将通过评估脐带/胎盘CYP酶/多态性来评估胎儿对这三种CYP酶活性变异的贡献。

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.