Alcohol and HIV protease inhibitors interactions

描述(由申请人提供)：艾滋病毒感染者对乙醇的使用有很大的兴趣和可能的担忧。乙醇可以诱导细胞色素P450(CYP)3A，这是一种负责HIV PI(HIV-PI)代谢的亚型。这项建议的目的是评估酒精消费对口服HIV-蛋白酶抑制剂的药代动力学的影响，特别是AUC和Cmax。这一目标有两个特定的目标，并在本申请中涉及，这将利用酒精消耗及其对药物处置的相互作用的两个啮齿动物模型。S.A.I：表征口服HIV蛋白酶抑制剂在喂含Leiber-DeCarli含乙醇饮食的大鼠中的药代动力学，以及配对喂养和即兴对照。之所以选择这个模型，是因为已经证明乙醇可以在没有明显肝脏病变的情况下诱导细胞色素P3A，可能类似于早期的酒精性疾病。 S.A.II：通过胃管饲喂乙醇和流食的方法，研究口服HIV蛋白水解酶抑制剂的大鼠的药代动力学。之所以选择这种乙醇消耗模型，是因为它被证明是更好的CYP3A诱导剂，还能引起实质性的肝脏病理1)表征和比较选择的HIV蛋白酶抑制剂(HIV-PI)，如沙奎那韦和吲地那韦，在这些长期喂养乙醇的模型(和对照)中口服后的药代动力学。我们还将确定三乙酰朗诺霉素(TAO)(一种CYP3A的特异性抑制剂)预处理对拉力给药的药代动力学的影响。2)表征和比较口服乙醇后萨奎那韦和吲哚那韦的药代动力学。3)验证TAO对这些大鼠肝脏和小肠细胞色素P3A的活性、含量的诱导和特异性抑制。由于副糖蛋白(PGP)可以影响HIV蛋白抑制剂的生物利用度，我们还将表征慢性乙醇对PGP含量的影响。目前，抗逆转录病毒药物治疗HIV疾病的成功已有文献记载。只有当抗病毒治疗的治疗水平保持不变时，这些好处才是成立的。对于那些接受治疗的人来说，了解药物相互作用和诱导HIV-PI代谢仍然是一个关键目标。许多服用这些药物的人也会急性和慢性地消耗乙醇。由于CYP3A4在HIV-PI药物代谢中的重要性，以及乙醇对其的诱导作用，HIV-PI与乙醇的相互作用具有临床意义，也是本研究的重点。

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.