AGING AND CYP-MEDIATED HERB-DRUG INTERACTIONS

由肝细胞色素P-450介导的药物相互作用引起的药物不良反应在老年人中普遍存在。随着草药膳食补充剂的广泛使用，潜在的草药-药物相互作用也成为一个重要的医学问题。 据估计，近五分之一服用处方药的人也服用草药补充剂。这意味着超过1500万成年人，包括近300万65岁或以上的成年人，他们同时服用处方药和草药补充剂。 此外，70%的患者没有向初级保健提供者透露他们的草药使用情况。 因此，潜在的草药相互作用的风险是相当大的。 这在老年人中尤其如此，他们不仅接受多种药物治疗，而且经常表现出肝脏药物清除率降低。在医学文献中越来越多地报道了记录在案的草药-药物相互作用，虽然一些体外研究表明，植物药的植物化学成分可以调节肝脏药物代谢酶（细胞色素P-450，CYP 1A 1），但尚未在人体中对这种相互作用的潜在机制进行前瞻性研究。 在这项研究中要检验的假设是，老年患者继发于草药介导的肝纤维化酶活性变化的草药-药物相互作用的风险增加。 目前的提案将利用表型探针药物的母体/代谢物比率来评估慢性草药补充对不同年龄的人类志愿者肝脏活性的影响。 本项目的目标是：（1）确定长期使用含有大蒜、银杏、人参或圣约翰草的膳食补充剂是否调节特定的肝脏活性（即CYP 1A 2、CYP 2D 6、CYP 2 E1和CYP 3A 4）;（2）衰老是否增强CYP介导的草药-药物相互作用的风险。

Adverse drug effects stemming from hepatic cytochrome P-450-mediated drug interactions are prevalent in the elderly. With the widespread use of herbal dietary supplements, potential herb-drug interactions are also emerging as a significant medical concern. It has been estimated that nearly 1 in 5 individuals taking prescription medications also take herbal supplements. This translates to more than 15 million adults, including nearly 3 million adults aged 65 years or older, who take prescription medications concurrently with herbal supplements. Furthermore, it has been noted that 70 percent of patients do not reveal their herb use to primary care providers. The risk of potential herb-drug interactions, therefore, is considerable. This is especially so in the elderly who not only receive multiple medications, but often exhibit reduced hepatic drug clearance. Documented herb-drug interactions are increasingly reported in the medical literature, and while a few in vitro studies indicate that the phytochemical components of botanical medicines can modulate hepatic drug metabolizing enzymes (cytochrome P-450s, CYP), no prospective studies into the mechanisms underlying such interactions have been conducted in humans. The hypothesis to be tested in this investigation is that elderly patients are at an increased risk for herb-drug interactions secondary to herb-mediated changes in hepatic CYP enzyme activity. The current proposal will utilize parent/metabolite ratios of phenotypic probe drugs to assess the effect chronic herbal supplementation has on hepatic CYP activity in human volunteers of varying age. The goals of this project are: (1) to determine if chronic usage of dietary supplements containing either garlic, gingko biloba, ginseng, or St. John's wort modulate specific hepatic CYP activities (i.e. CYP1A2, CYP2D6, CYP2E1, and CYP3A4); and (2) whether aging potentiates the risk of CYP-mediated herb-drug interactions.