Alcohol and HIV protease inhibitors interactions

酒精和 HIV 蛋白酶抑制剂的相互作用

• 批准号: 6668674
• 负责人: DENNIS E FEIERMAN
• 金额: $ 8.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668674
• 关键词: AIDS therapy; HIV infections; alcoholic beverage consumption; alcoholic liver cirrhosis; antiAIDS agent; cytochrome P450; drug interactions; ethanol; fluorescence; gene induction /repression; glycoproteins; high performance liquid chromatography; indinavir; laboratory rat; liver; macrolide antibiotics; oral administration; pharmacokinetics; protease inhibitor; saquinavir; small intestines; tube feeding; western blottings

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.

描述（由申请人提供）：艾滋病毒感染患者使用乙醇引起了极大的兴趣和可能的关注。 乙醇已显示出诱导细胞色素P450（CYP）3A，这是一种负责HIV PIS（HIV-PIS）代谢的同工型。 该提案的目的是评估乙醇消耗对口服HIV-蛋白酶抑制剂的药代动力学，特别是AUC和CMAX的影响。 从这个目标中得出了两个具体的目标，并在此应用中解决了该目标，该目标将利用两种啮齿动物的乙醇消耗模型及其在药物处置上的互动。 选择该模型是因为已经显示乙醇可以诱导CYP3A而没有明显的肝脏病理学，并且可能类似于早期酒精疾病。 S.A.II：通过胃内管喂养方法来表征大鼠口服艾滋病毒蛋白酶抑制剂的药代动力学。 选择了这种乙醇消耗模型，因为它已被证明是CYP3A的更好诱导剂，并且还会引起大量的肝脏病理学。1）表征并比较精选的HIV蛋白酶抑制剂（HIV-PI）的药代动力学（HIV-PI），例如saquinavir和Indinavir，例如在这些模型中使用这些模型（和对照组）（和对照）（和对照组）乙醇。 我们还将确定特异性CYP3A的特定抑制剂Triacetyloyeandomycin（TAO）对Rally施用的Saquinavir和Indinavir的药代动力学的影响。 Tao在肝脏中对CYP3A的CYP3A活性，含量和特异性抑制作用，而小肠中的小肠则是CYP3A。 由于para-糖蛋白（PGP）会影响HIV蛋白酶抑制剂的生物利用度，因此我们还将表征慢性乙醇对PGP含量的影响。现在有充分的文献记录了抗逆转录病毒药物治疗HIV-疾病症治疗HIV-疾病症的成功。 只有在维持抗病毒治疗的治疗水平时，这些好处才可以持续下去。 对于那些接受治疗的人来说，了解药物相互作用和HIV-PI代谢的诱导仍然是一个关键目标。 许多服用这些药物的人也急性和长期食用乙醇。 由于CYP3A4在HIV-PI药物代谢方面的重要性以及乙醇的诱导，HIV-PI和乙醇的相互作用具有临床重要性，并且是该提案的主要重点。