GARLIC PREPARATIONS AND ANTIRETROVIRAL DRUGS

大蒜制剂和抗逆转录病毒药物

• 批准号: 6582651
• 负责人: DAVID J GREENBLATT
• 金额: $ 35.66万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6582651
• 关键词: AIDS therapy; HIV infections; P glycoprotein; SDS polyacrylamide gel electrophoresis; alternative medicine; angiosperms; antiAIDS agent; antiviral agents; biological products; blood chemistry; clearance rate; clinical research; combination therapy; cytochrome P450; drug interactions; drug metabolism; enzyme induction /repression; human subject; midazolam; pharmacokinetics; physical chemical interaction; protein isoforms; ritonavir; saquinavir; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The use of complementary and alternative medical (CAM) therapies, including botanical medicines, is increasing continuously. Botanical medicines are of particular importance, since these natural preparations may cause clinically important drug interactions with prescription drugs, in particular the antiretroviral drugs that have become the principal medical treatment for individuals with HIV infection and AIDS. This population commonly uses additional CAM treatments, including botanical medicines. Garlic is commonly taken by patients with HIV, and garlic has been shown to interact with saquinavir. The broad objective of this project is to develop and test research models to enhance mechanistic understanding of interactions between botanicals and antiretrovirals, such that clinically important interactions can be anticipated and prevented. We propose a combined experimental and clinical approach to evaluating the influence of garlic, and of selected chemical components of garlic, on the processes regulating disposition of the majority of antiretroviral agents (metabolism by CYP3A and transport by P-glycoprotein), and on the pharmacokinetics of two representative antiretrovirals, ritonavir and saquinavir. There are two specific aims. The experimental component will assess the effect of two garlic preparations (standardized garlic and aged garlic extract), and several individual chemical components, in the following systems: inhibitory actions on human CYP3A (and other CYPs) in human liver microsomes; induction of CYP3A in primary human hepatocyte culture; inhibition of P-gp transport in Caco-2 transwell cultures; and induction of P-gp expression in LS180V transwell cell cultures. In clinical studies of healthy human volunteers, we will study the effect of 14 days of exposure to standardized garlic, aged garlic extract, and placebo on: the clearance of oral midazolam, a CYP3A probe substrate; the clearance of oral fexofenadine, a probe P-gp substrate; and the pharmacokinetics of ritonavir and saquinavir, representative antiretrovirals dependent on CYP3A and P-gp for disposition and clearance. Kinetics of these compounds are determined prior to, during, and after garlic exposure. The work will provide immediately applicable clinical data on garlic interactions with antiretrovirals, as well as mechanistic data identifying the interaction process and its predictability from in vitro models.

描述（由申请人提供）：补充和替代医学（CAM）疗法（包括植物药物）的使用正在不断增加。植物药物尤其重要，因为这些天然制剂可能会与处方药（特别是已成为艾滋病毒感染者和艾滋病患者主要治疗药物的抗逆转录病毒药物）产生临床上重要的药物相互作用。该人群通常使用额外的 CAM 治疗，包括植物药物。艾滋病毒患者通常服用大蒜，并且大蒜已被证明与沙奎那韦相互作用。该项目的总体目标是开发和测试研究模型，以增强对植物药和抗逆转录病毒药物之间相互作用的机制理解，从而可以预测和预防临床上重要的相互作用。我们提出了一种实验和临床相结合的方法来评估大蒜和大蒜的选定化学成分对大多数抗逆转录病毒药物的调节过程（CYP3A 代谢和 P-糖蛋白转运）以及药代动力学的影响两种代表性的抗逆转录病毒药物，利托那韦和沙奎那韦。有两个具体目标。实验部分将评估两种大蒜制剂（标准化大蒜和陈化大蒜提取物）以及几种单独的化学成分在以下系统中的作用：对人肝微粒体中人 CYP3A（和其他 CYP）的抑制作用；在原代人肝细胞培养物中诱导 CYP3A； Caco-2 transwell 培养物中 P-gp 转运的抑制；以及在 LS180V transwell 细胞培养物中诱导 P-gp 表达。在健康人类志愿者的临床研究中，我们将研究接触标准化大蒜、陈化大蒜提取物和安慰剂 14 天对以下方面的影响： 口服咪达唑仑（一种 CYP3A 探针底物）的清除率；口服非索非那定（探针 P-gp 底物）的清除率；以及利托那韦和沙奎那韦的药代动力学，这两种代表性抗逆转录病毒药物依赖 CYP3A 和 P-gp 进行处置和清除。这些化合物的动力学是在接触大蒜之前、期间和之后测定的。这项工作将提供有关大蒜与抗逆转录病毒药物相互作用的立即适用的临床数据，以及从体外模型中识别相互作用过程及其可预测性的机制数据。