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

圣约翰草和男性 CYP3A 代谢

• 批准号: 6539256
• 负责人: REGINALD F FRYE
• 金额: $ 33.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6539256
• 关键词: alternative medicine; angiosperms; anticonvulsants; caffeine; cytochrome P450; depression; drug interactions; drug metabolism; enzyme induction /repression; human subject; midazolam; patient oriented research; pharmacokinetics; plant extracts; saccades

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).

描述（逐字从应用程序）：草药圣约翰 在美国，麦芽汁在柜台上出售， 和科学的关注，因为它在治疗抑郁症方面的潜在用途。 事实上，NIMH正在赞助这个国家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作用机制和治疗机制， 潜在的圣约翰草，药物之间的相互作用的潜力， 草药和其他药物，包括抗抑郁药， 基本上被忽视了。有证据表明，圣约翰草诱导 细胞色素P450（CYP）酶系统，包括最常见的CYP 3A酶 肠和肝中有丰富的胰蛋白酶。的主要决定因素 CYP代谢药物的循环浓度是CYP活性 内切酶圣约翰草可能会诱导代谢的共同管理 药物对于那些可能接受 包括抗抑郁药在内的多种药物，主要由 酵素。β-淀粉样蛋白酶的诱导将导致β-淀粉样蛋白浓度的降低， 联合用药和代谢物浓度增加， 这可能影响功效和/或毒性。第一个具体目标是评估 给予咪达唑仑后圣约翰草对CYP 3A代谢的影响 随机化平行组受试者在接受 安慰剂-或圣约翰草，两个剂量（300和600 tid，持续两周）。 药代动力学和药效学指标（扫视眼球运动） 将使用咪达唑仑。第二个具体目标是研究 圣约翰草对其他代谢途径，特别是CYP 1A 2，使用咖啡因作为一种 探针，使用氟比洛芬作为探针的CYP 2C 9和使用美芬妥英作为探针的CYP 2C 19。 在咪达唑仑研究后的第二天使用“鸡尾酒”探针方法。在 具体目标3，研究人员提出验证一种新方法， 使用以下方法表征肝和肠的体内CYP 3A活性 半同时静脉内和口服咪达唑仑给药（口服咪达唑仑 然后在口服给药后6小时静脉注射），并将其与单独的一天进行比较 静脉注射和口服咪达唑仑（具体目标3）。