PHARMACOKINETICS AND PHARMACODYNAMICS

艾滋病毒疾病的管理涉及抗逆转录病毒的联合方案 包括蛋白酶抑制剂在内的药物。从药理上讲，这些化合物 是令人感兴趣的，关于如何最好地确保 它们的最佳使用。从药动学上讲，这些蛋白水解酶抑制剂很容易 药物的相互作用，因为这些药物在代谢上是复杂的 主要由细胞色素P450同工酶代谢。此外，问题还包括 与总体药物暴露的关系以及这与临床的关系 结果(药效学)是重要的，因为次佳暴露(例如 药物水平低和/或依从性差)可导致 抗药性，而过度暴露(例如高药物水平)可能会导致 对毒性的影响。药代动力学变化和变异性 遵守规定的方案(两种不同的成分)可能会影响 暴露这些药物及其侮辱性的临床效果。 乙醇是艾滋病毒感染者滥用的物质，它可能会改变 这些药物的药代动力学可以通过诱导药物代谢来实现 在酒精含量极高的情况下观察到。这个项目将 研究这些潜在的乙醇影响，并确定 抗病毒药物在慢性阻塞性肺疾病患者中的药代动力学和药效学研究 酒精使用者与轻饮者/非饮酒者的比较。药代动力学 该项目的组成部分将包括药物动力学评价 慢性酒精使用者急性联合运动期间的蛋白水解酶抑制物 用乙醇给药，以及在没有极高 酒精水平，以研究潜在的代谢抑制和 乙醇的诱导作用。这些数据将与 在饮酒者和不饮酒者中使用这两种人群获得的结果 药代动力学测量以及依从性信息，以便 可以估计总体的毒品暴露情况。这反过来又将在 具有临床反应措施的计划项目(与 中枢神经系统和三叉神经节的艾滋病毒发病率)。最后，这些问题的处理 将对脑脊液中的药物进行调查。该项目将提供重要的 慢性重度酒精摄入对机体代谢和代谢影响的数据 HIV疾病的抗逆转录病毒药物的疗效。

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.