GARLIC PREPARATIONS AND ANTIRETROVIRAL DRUGS

描述(由申请人提供)：补充和替代医学(CAM)疗法的使用，包括植物药物，正在不断增加。植物药特别重要，因为这些天然制剂可能会导致临床上重要的药物与处方药的相互作用，特别是已成为艾滋病毒感染和艾滋病患者的主要治疗方法的抗逆转录病毒药物。这一人群通常使用额外的CAM治疗，包括植物药物。大蒜通常是艾滋病毒患者服用的，而且大蒜已被证明与沙奎那韦相互作用。该项目的主要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理理解，从而能够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部分化学成分对大多数抗逆转录病毒药物的代谢调节过程(通过细胞色素P3A代谢和P-糖蛋白转运)的影响，以及对两种典型抗逆转录病毒药物利托那韦和沙奎那韦的药代动力学的影响。有两个具体目标。实验部分将评估两种大蒜制剂(标准大蒜和陈蒜提取物)和几种单独的化学成分在以下系统中的效果：在人肝微粒体中对人细胞色素P3A(和其他细胞色素P450)的抑制作用；在原代培养的人肝细胞中诱导细胞色素P3A；抑制Caco-2 Transwell细胞中的P-gp转运；以及诱导LS180V Transwell细胞中P-gp的表达。在健康人体志愿者的临床研究中，我们将研究14天暴露于标准大蒜、陈化大蒜提取物和安慰剂对以下方面的影响：口服咪达唑仑(一种CYP3A探针底物)的清除；口服非索非那定(一种探针P-gp底物)的清除；以及利托那韦和沙奎那韦(依赖于CyP3A和P-gp的处置和清除的代表性抗逆转录病毒药物)的药代动力学。这些化合物的动力学是在大蒜暴露之前、期间和之后进行测定的。这项工作将提供大蒜与抗逆转录病毒药物相互作用的直接适用的临床数据，以及从体外模型识别相互作用过程及其可预测性的机制数据。

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.