OBSTETRICS FETAL PHARMACOLOGY RESEARCH NETWORK UNIT PITTSBURGH COCKTAIL

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的目的是测试狒狒模型作为人类药物代谢酶诱导的替代品，以及怀孕对这些酶诱导变化的影响。这是一项简单的研究，旨在测试含有咖啡因、氟比洛芬、外消旋/美苯妥英、德异喹、氯唑酮和氨苯砜（用于非孕妇）的传统六药匹兹堡鸡尾酒与含有咖啡因、氟比洛芬、奥美拉唑、美托洛尔、对乙酰氨基酚和红霉素的孕妇鸡尾酒。选择这些特异性药物是因为它们可以评估P450酶系统的几个元素，包括CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A。虽然这两种鸡尾酒的设计目的是观察同一种酶的酶诱导，但怀孕鸡尾酒从未进行过实际测试。预计狒狒将被证明是一个很好的模型，两种匹兹堡鸡尾酒将是等效的。随后，随着可能获得FDA批准的新药的出现，狒狒将成为测试怀孕对这些药物代谢影响的绝佳模型，特别是通过这些P450酶的代谢机制。这项研究的潜力是巨大的，因为它很可能表明狒狒是一个极好的模型，用于研究药物代谢动力学和药效学在怀孕期间的纵向变化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this study is to test the baboon model as a surrogate for the human as regards induction of drug metabolizing enzymes and the effects of pregnancy upon changes in induction of these enzymes. This is a simple study designed to test the conventional 6-drug Pittsburg cocktail containing caffeine, flurbiprofen, racemic/mephenytoin, debrisoquine, chlorozoxazone, and dapsone (as used in non-pregnant women) against a cocktail that is designed to be used in pregnancy that consists of caffeine, flurbiprofen, omeprazole, metoprolol, acetaminophen, and erythromycin. These specific drugs are chosen as they will allow evaluation of several elements of the P450 enzyme system to include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. While the two cocktails are designed to look at enzyme induction of the same exact enzymes, the pregnancy cocktail has never actually been tested. It is anticipated that the baboon will prove to be an excellent model and that the 2 Pittsburg cocktails will be equivalent. Subsequently, as new drugs become available that will likely receive FDA approval the baboon will serve as an excellent model for testing the effects of pregnancy upon metabolism of these drugs and specifically the mechanism of metabolism via these P450 enzymes. The potential of this study is substantial inasmuch as it is likely to show the baboon to be an excellent model for study of changes in pharmacokinetics and pharmacodynamics longitudinally across pregnancy.