Alcohol and HIV protease inhibitors interactions

酒精和 HIV 蛋白酶抑制剂的相互作用

• 批准号: 6466027
• 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/6466027
• 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）： HIV 感染者对乙醇的使用引起了极大的兴趣和可能的担忧。 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。 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。 该目标衍生出两个具体目标，并在本申请中得到解决，该申请将利用两种啮齿动物模型的乙醇消耗及其对药物处置的相互作用。S.A.I：表征口服 HIV 蛋白酶抑制剂在喂食 Leiber-DeCarli 含乙醇饮食、配对喂养和随意对照的大鼠中的药代动力学。 选择该模型是因为已经证明乙醇可以诱导 CYP3A 而没有明显的肝脏病理学变化，并且可能类似于早期酒精病。 S.A.II：为了表征通过胃管饲喂方法饲喂乙醇和液体饮食的大鼠口服 HIV 蛋白酶抑制剂的药代动力学。 选择这种乙醇消耗模型是因为它已被证明是 CYP3A 的更好诱导剂，并且还会引起严重的肝脏病理学。1) 在这些长期喂食乙醇的模型（和对照）中口服给药后，表征并比较选定的 HIV 蛋白酶抑制剂 (HIV-PI)（例如沙奎那韦和茚地那韦）的药代动力学。 我们还将确定三乙酰竹桃霉素 (TAO)（一种 CYP3A 特异性抑制剂）预处理对沙奎那韦和茚地那韦的药代动力学的影响。2) 在这些模型中与乙醇联合口服后，表征并比较沙奎那韦和茚地那韦的药代动力学。3) 验证 这些大鼠肝脏和小肠中CYP3A的活性、含量以及TAO对CYP3A的特异性抑制。 由于对糖蛋白 (pgp) 可以影响 HIV 蛋白酶抑制剂的生物利用度，我们还将描述长期乙醇对 pgp 含量的影响。抗逆转录病毒药物治疗 HIV 疾病的成功现已得到充分证明。 只有维持抗病毒治疗的治疗水平时，这些益处才能维持。 了解药物相互作用和 HIV-PI 代谢的诱导仍然是接受治疗的个体的一个关键目标。 许多服用这些药物的人也会急性或长期消耗乙醇。 由于 CYP3A4 对 HIV-PI 药物代谢的重要性以及乙醇对其的诱导作用，HIV-PI 和乙醇的相互作用具有临床重要性，也是本提案的主要焦点。