St. John's Wort and CYP3A Metabolism in Men & Women

描述(来自应用程序的逐字)：草药圣约翰 麦芽汁在美国的柜台上出售，吸引了大量的消费者 并因其在抑郁症治疗中的潜在应用而受到科学关注。 事实上，NIMH正在赞助该国的第一个多中心试验 评价圣约翰草治疗抑郁症的疗效。 虽然许多工作已经研究了它的作用机制和治疗 圣约翰麦芽汁的潜力，药物之间相互作用的潜力 草药和其他药物，包括抗抑郁药，已经被 基本上被忽视了。有证据表明，圣约翰的麦芽汁可以诱导 细胞色素P450(CYP)酶系包括细胞色素P3A酶，它们是最多的 肠道和肝脏中都含有丰富的CYP酶。一个主要的决定因素 CYP代谢药物的循环浓度就是CYP的活性 酵素。圣约翰草可能诱导联合给药的代谢。 药物对抑郁症患者尤其重要，因为他们可能会接受 多种药物，包括抗抑郁药，主要由 CYP酶。CYP酶的诱导会导致浓度降低 联合给药和增加代谢物浓度，每一种 这可能会影响疗效和/或毒性。第一个具体目标是评估 咪达唑仑对小鼠肝细胞色素P3A代谢的影响 随机平行分组的受试者在接受治疗前和之后 安慰剂-或圣约翰麦芽汁，两次剂量(300和600，tid，两周)。 的药代动力学和药效学指标(眼球跳动) 咪达唑仑将被执行。第二个具体目标是研究 圣约翰麦芽汁在其他CYP途径上的作用，特别是使用咖啡因作为 探针，以氟比洛芬为探针的CYP2C9和以美苯妥因为探针的CYP2C19 在咪达唑仑研究后的第二天采用“鸡尾酒”探针法。在……里面 具体目标3，调查人员建议验证一种新的方法 体内肝脏和肠道细胞色素P3A活性的研究 半同步静脉注射。和口服咪达唑仑(口服咪达唑仑 然后是静脉注射。在口服后6小时)，并将其与单独的一天进行比较 静脉注射给药。和口服咪达唑仑(特定目标3)。

DESCRIPTION (Verbatim from the application): The herbal medicine St. John's Wort, sold over the counter in the United States, has attracted tremendous lay and scientific attention for its potential use in the treatment of depression. Indeed, NIMH is sponsoring the first multi-center trial in this country evaluating the efficacy of St. John's wort for the treatment of depression. While much work has investigated the mechanism of action and therapeutic potential of St. John's wort, the potential for drug interactions between this herbal medicine and other medicines, including anti-depressants, has been largely ignored. There is evidence to suggest that St. John's wort induces the cytochrome P450 (CYP) enzyme system including CYP3A enzymes, which are the most abundant CYP enzymes in both the intestine and liver. A major determinant of the circulating concentrations of CYP-metabolized drugs is the activity of CYP enzymes. That St. John's wort may induce the metabolism of co-administered drugs would be of particular importance in depressed patients who may receive multiple drugs including anti-depressants, which are primarily metabolized by CYP enzymes. Induction of CYP enzymes would lead to decreased concentrations of co-administered drugs and increased concentrations of metabolites, each of which may affect efficacy and/or toxicity. The first specific aim is to assess effects of St John's wort on CYP3A metabolism by administering midazolam to subjects in randomized parallel groups before and after receiving either placebo- or St. John's Wort at two doses (300 and 600 tid for two weeks). Pharmacokinetics and pharmacodynamic measures (saccadic eye movements) of midazolam will be performed. The second specific aim is to study the effects of St. John's Wort on other CYP pathways, specifically CYP1A2 using caffeine as a probe, CYP2C9 using flurbiprofen as a probe, and CYP2C19 using mephenytoin as a "cocktail" probe approach on the day following the midazolam studies. In specific aim 3, the investigator proposes to validate a new method for characterizing both hepatic and intestinal in vivo CYP3A activity using semisimultaneous i.v. and oral midazolam administration (oral midazolam followed by i.v. at 6 hr after oral dosing) and comparing this to separate day administration of i.v. and oral midazolam (Specific Aim 3).