Garlic Metabolism and Cytochrome P450 Modulation

描述（由申请人提供）：大蒜补充剂广泛用于治疗高血胆固醇和血脂。直到最近，大蒜补充剂被认为耐受性良好，相对安全。大蒜补充剂和几种狭义的治疗药物之间的不良相互作用，包括抗凝剂（华法林，氟茚二酮）和艾滋病毒蛋白酶抑制剂（沙奎那韦，利托那韦），在过去的2年中已被报道。动物和体外研究已知大蒜的有机硫成分，以及大蒜提取物，已知同时抑制和诱导几种酶（1A，2B，2C，2 E和3A亚家族）在肝脏中，以及外排转运蛋白P-葡萄糖蛋白（Pgp）在肠粘膜。然而，最近对人类受试者的研究产生了关于大蒜补充剂对细胞色素P450功能的影响的相互矛盾的数据。我们的具体假设是：1）大蒜补充剂对CYP 3A 4和Pgp功能的影响随大蒜制剂的类型（即大蒜粉、蒸汽蒸馏大蒜油和老化大蒜）而变化; 2）大蒜的作用是时间和方案依赖性的（例如，它急性抑制和慢性诱导人类受试者的CYP 3A 4和Pgp活性）。将在每天摄入大蒜补充剂期间和停止后不久的不同时间向一组健康人类志愿者施用两种单独的大蒜素和Pgp探针底物的“鸡尾酒”，包括咖啡因（1A 2）、安非他酮（2B 6）、氯唑沙宗（2 E1）、甲苯磺丁脲（2C 9）、奥美拉唑（2C 19）、美托洛尔（2D 6）、咪达唑仑（3A 4/5）和地高辛（Pgp）。通过收集血液、呼吸和尿液样本，同时研究已知的生物活性大蒜成分及其生物转化产物的药代动力学。大蒜代谢物数据可能提供线索，大蒜衍生化合物可能负责推定的代谢作用。具体来说，我们将测量来自大蒜素和烯丙基硫化物的代谢产物，它们是大蒜粉和大蒜油的主要成分。我们还将测量S-烯丙基半胱氨酸的代谢产物，其来自大蒜粉和老化大蒜中的烯丙基半胱氨酸肽的水解。这些人类受试者代谢研究将在华盛顿大学综合临床研究中心进行。这些结果将为进一步临床研究的设计提供关键信息，以表征和阐明潜在的重要大蒜-药物不良相互作用。

DESCRIPTION (provided by applicant): Garlic supplements are widely used for the treatment of high blood cholesterol and lipids. Until recently, garlic supplements were thought to be well tolerated and relatively safe. Adverse interactions between garlic supplements and several narrow therapeutic drugs, including anticoagulants (warfarin, fuindione) and HIV protease inhibitors (saquinavir, ritonavir), have been reported within the past 2 years. Animal and in vitro studies with known organosulfur constituents of garlic, as well as garlic extracts, are known to simultaneously inhibit and induce several CYP enzymes (1A, 2B, 2C, 2E and 3A subfamilies) in the liver, as well as the efflux transporter P-gylcoproptein (Pgp) in the intestinal mucosa. However, very recent studies in human subjects have produced conflicting data as to the effects of garlic supplements on cytochrome P450 function. Our specific hypotheses are: 1) the effects of garlic supplements on CYP and Pgp function vary with the type of garlic preparation (viz. garlic powder, steamed-distilled garlic oil, and aged garlic); and 2) garlic's effect is time- and regimen-dependent (e.g. it acutely inhibits and chronically induces CYP3A4 and Pgp activities in human subjects). Two separate "cocktails" of CYP and Pgp probe substrates, including caffeine (1A2), buproprion (2B6), chlorzoxazone (2E1), tolbutamide (2C9), omeprazole (2C19), metoprolol (2D6), midazolam (3A4/5), and digoxin (Pgp), will be administered to a panel of healthy human volunteers at various times during and shortly after discontinuation of daily intake of garlic supplement. Pharmacokinetics of known bioactive garlic constituents and their biotransformation products will be simultaneously studied through collection of blood, breath and urine samples. Garlic metabolite data may offer clues as to which garlic-derived compounds may be responsible for the putative metabolic effects. Specifically, we will measure metabolites deriving from allicin and allylic sulfides, which are the main constituents of garlic powder and garlic oil. We will also measure metabolites of S-allylcysteine, which is derived from hydrolysis of allylic cysteinyl peptides in garlic powder and aged garlic. These metabolic studies in human subjects will be conducted at the University of Washington General Clinical Research Center. The results will provide critical information for the design of further clinical studies to characterize and elucidate potentially important adverse garlic-drug interactions.