PRECLINICAL PHARMACOLOGICAL STUDIES

合理药物开发策略的一个重要组成部分是 研究药物的毒性和治疗作用的相关性 在动物体内的血浆和组织浓度。一个成功 这种方法的结果在很大程度上取决于敏感的可用性， 定量生物基质中化合物的方法和仔细的 临床前药理学和毒理学研究的整合。这 合同提供了持续的资源， 正在考虑的抗肿瘤和抗艾滋病毒药物的药理学研究 由发展治疗学项目资助分析方法 用于定量血浆、尿液、其他生物液体 和/或组织的水平， 体外和体内评价确定的毒性范围。血浆 稳定性和蛋白结合研究在早期阶段进行， 复合发展然后计算测试化合物的药代动力学。 在啮齿类动物、犬和非人灵长类动物中进行评价， 通过各种途径和时间表给药，特别是那些打算 用于临床试验。对于某些化合物，特别是抗艾滋病毒 药物，口服（或其他非胃肠外）生物利用度的测定是 重点介绍为了更好地预测新药物的人体药理学， 在临床试验之前，比较代谢研究是 使用动物和人肝脏，用选定的化合物进行 准备工作 通过该合同获得的数据也有助于 药理学指导的剂量递增策略在 I期临床试验。

An important component of a rational drug development strategy is the correlation of toxic and therapeutic effects of investigational agents with their plasma and tissue concentrations in animals. A successful outcome of this approach depends heavily on the availability of sensitive methods for quantitating compounds in biological matrices and the careful integration of preclinical pharmacology and toxicology studies. This contract provides a continuing resource for conducting defined pharmacology studies of antitumor and anti-HIV agents under consideration by the Developmental Therapeutics Program. Analytical methods are developed to quantify compounds in plasma, urine, other biological fluids, and tissues at levels corresponding to the expected therapeutic and/or toxic range as determined from in vitro and in vivo evaluations. Plasma stability and protein binding studies are conducted at an early stage of compound development. The pharmacokinetics of test compounds are then evaluated in rodents, dogs, and non-human primates following administration by various routes and schedules, especially those intended for use in clinical trials. For some compounds, particularly anti-HIV agents, determination of oral (or other non-parenteral) bioavailability is emphasized. To provide better predictions of the human pharmacology of new agents prior to clinical trial, comparative metabolism studies are conducted with selected compounds using animal and human liver preparations. Data obtained through this contract also facilitates the application of pharmacologically-guided dose escalation strategies in Phase I clinical trials.