Alcohol and HIV protease inhibitors interactions

描述（由申请人提供）：HIV感染者对乙醇的使用有很大的兴趣和可能的关注。乙醇已被证明可以诱导细胞色素P450 (CYP) 3A，这是一种负责HIV- pi （HIV- pi）代谢的异构体。本提案的目的是评估乙醇消耗对口服hiv蛋白酶抑制剂药代动力学的影响，特别是AUC和Cmax。从这个目标衍生出两个特定的目标，并在本应用程序中解决，将利用两种啮齿动物模型的乙醇消耗及其对药物配置的相互作用。s.a.i：表征口服给药的HIV蛋白酶抑制剂在饲喂leber - decarli含乙醇饮食的大鼠中的药代动力学，以及配对喂养和ad-lib对照。之所以选择这个模型，是因为有研究表明，乙醇可以诱导CYP3A，而不会引起明显的肝脏病理，可能类似于早期酒精疾病。

DESCRIPTION (provided by applicant): There is great interest and possible concern in the use of ethanol by HIV infected patients. Ethanol has been shown to induce cytochrome P450 (CYP) 3A, an isoform responsible for the metabolism of HIV PIs (HIV-PIs). The goal of this proposal is to evaluate the effects of ethanol consumption on the pharmacokinetics, specifically AUC and Cmax, of orally administered HIV-protease inhibitors. Two specific objectives are derived from this goal and are addressed in this application that will utilize two rodent models of ethanol consumption and its interaction on drug disposition.S.A.I: To characterize the pharmacokinetics of orally administered HIV protease inhibitors in rats fed the Leiber-DeCarli ethanol-containing diet, and pair fed and ad-lib controls. This model was chosen since it has been shown that ethanol can induce CYP3A without significant liver pathology and may be analogous to early alcohol disease. S.A.II: To characterize the pharmacokinetics of orally administered HIV protease inhibitors in rats fed ethanol and liquid diet via the intragastric tube feeding method. This model of ethanol consumption was chosen since it has been shown to be a better inducer of CYP3A and also cause substantial liver pathology.1) Characterize and compare the pharmacokinetics of select HIV protease inhibitors (HIV-PI) such as saquinavir and indinavir after their oral administration in these models (and controls) chronically fed ethanol. We will also ascertain the effects of pretreatment with triacetyloleandomycin (TAO), a specific inhibitor of CYP3A, on the pharmacokinetics of rally administered saquinavir and indinavir.2) Characterize and compare the pharmacokinetics of saquinavir and indinavir after oral co-administration with ethanol in these models.3) Validate the induction of CYP3A activity, content and specific inhibition of CYP3A by TAO in liver and small bowel in these rats. Since para-glycoprotein (pgp) can affect the bioavailability of HIV protease inhibitors we will also characterize the effects of chronic ethanol on pgp content.The success of antiretroviral medication therapies for the treatment of HIV-disease is now well documented. These benefits are only tenable when therapeutic levels of the antiviral treatments are maintained. Understanding drug interactions and induction of HIV-PI metabolism remains a critical goal for those individuals receiving treatment. Many individuals taking these medications also consume ethanol, acutely and chronically. Because of the importance of CYP3A4 with respect to HIV-PI drug metabolism, and its induction by ethanol, the interactions of HIV-PI and ethanol are of clinical importance and are the major focus of this proposal.