PHARMACOKINETICS AND PHARMACODYNAMICS

艾滋病毒疾病的管理涉及抗逆转录病毒药物的联合疗法， 包括蛋白酶抑制剂在内的药物。在药理学上，这些化合物 是有意义的，还有一些问题是如何最好地保证 的最佳使用。在药代动力学上，蛋白酶抑制剂 药物相互作用，因为这些药物是复杂的代谢， 主要由细胞色素P450同工酶代谢。此外，问题 与总体药物暴露的关系以及这与临床 结果（药效学）是重要的，因为次优暴露（例如， 药物水平低和/或依从性差）可导致 耐药性，而过度暴露（例如高药物水平）可能导致 毒性。药代动力学变化以及 遵守规定的方案（两个单独的组成部分）可能会影响 这些药物的暴露及其侮辱性的临床效果。 乙醇是艾滋病病毒感染者滥用的物质， 这些药物的药代动力学或者通过诱导药物代谢， 在急性高乙醇水平下观察到。该项目将 研究这些潜在的乙醇效应，并确定 这些抗病毒药物在慢性 酒精使用者与轻度/非饮酒者相比。药代动力学 该项目的组成部分将包括药物的药代动力学评价 蛋白酶抑制剂在慢性乙醇使用者急性共 与乙醇的管理，以及在没有急性高 水平的乙醇，以研究潜在的代谢抑制和 乙醇的诱导作用。数据将与 在轻度/非饮酒者中获得的结果，使用两种人群 药代动力学测量以及依从性信息， 可以估计总体药物暴露。这反过来又将与 临床反应措施的计划项目（与 CNS和PNS的HIV疾病发病率）。最后，对这些 将研究CSF中的药物。该项目将提供重要的 长期大量使用乙醇对代谢的影响数据， 抗逆转录病毒药物对艾滋病毒疾病的疗效。

Management of HIV disease involves combination regimens of antiretroviral drugs including the protease inhibitors. Pharmacologically these compounds are of interest and a number of questions remain as to how best assure their optimal use. Pharmacokinetically, the protease inhibitors are prone to drug interactions as these drugs are complex metabolically being primarily metabolized by cytochrome P450 isozymes. In addition, issues relation to overall drug exposure and how this correlates with clinical outcome (pharmacodynamics) is of importance as suboptimum exposure (e.g. low drug levels and/or poor adherence) can result in the development of drug resistance while excessive exposure (e.g. high drug levels) may lead to toxicity. Both pharmacokinetic changes as well as variability in adherence to prescribed regimens (two separate components) can impact on exposure of these drugs and their insulting clinical effect. Ethanol is a substance of abuse for HIV infected patients and it may alter the pharmacokinetics of these drugs either by inducing drug metabolism as observed in the present of acutely high ethanol levels. This project will investigate these potential ethanol effects and determine the pharmacokinetics and pharmacodynamics of these antivirals in chronic ethanol users as compared to light/non-drinkers. The pharmacokinetic component of this project will include pharmacokinetic evaluations of the protease inhibitors in chronic ethanol users during acute co- administration with ethanol, as well as in the absence of acutely high levels of ethanol, to investigate the potential metabolic inhibiting and inducing effects of ethanol respectively. The data will be compared to results obtained in light/nondrinkers, using both population pharmacokinetic measurements as well as information on adherence so that overall drug exposure can be estimated. This in turn will be correlated in the Program Project with measures of clinical response (relating to the CNS and PNS morbidity of HIV disease). Finally, the disposition of these drugs in the CSF will be investigated. This project will provide important data on the effect of chronic heavy ethanol use on the metabolism and efficacy of anti-retroviral agents for HIV disease.