Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans
Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans
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DOI：
10.1067/mcp.2002.126913
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发表时间：
2002-09-01
影响因子：
6.7
通讯作者：
Ang, CYW
中科院分区：
文献类型：
--
作者：
Gurley, BJ;Gardner, SF;Ang, CYW
目的：植物化学物质介导的细胞色素P450（CYP 450）活性调节可能是许多中药相互作用的基础。使用单个时间点表型代谢率来确定长期补充圣约翰草、大蒜油、人参和银杏叶是否影响CYP 1A 2、CYP 2D 6、CYP 2 E 1或CYP 3A 4活性。方法：12名健康志愿者（6名女性）被随机分配接受圣约翰草、大蒜油、人参或银杏叶28天。对于每例受试者，在每个补充阶段之间插入30天洗脱期。在补充前（基线）和补充结束时给予咪达唑仑、咖啡因、氯唑沙宗和异喹胍（INN，异喹胍）的探针药物鸡尾酒。使用1-羟基咪达唑仑/咪达唑仑血清比值测定补充前和补充后的CYP 3A 4、CYP 1A 2、CYP 2 E1和CYP 2D 6表型性状测量值（1小时样本），副黄嘌呤/咖啡因血清比值（6小时样本），6-羟基氯唑沙宗/氯唑沙宗血清比值（2小时样本）和异喹胍尿回收率（8小时收集）。补充前后的比较表明，圣约翰草显著诱导了CYP 2 E1和CYP 3A 4的活性（P < .0001）。在女性受试者中，圣约翰草产生的CYP 3A 4表型比率显着增加，似乎与体重指数无关。这一发现提示CYP 3A 4诱导的性二态性。大蒜油降低CYP 2 E1活性的39%（P = .030），而没有显着的影响，观察到的P人参和G biloba.Conclusions：单时间点的表型代谢率可以提供一个实用的方法预测CYP介导的草药在人类的药物相互作用。
Objectives: Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Single-time point phenotypic metabolic ratios were used to determine whether long-term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.Methods: Twelve healthy volunteers (6 females) were randomly assigned to receive either St John's wort, garlic oil, P ginseng, or G biloba for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe-drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were administered before supplementation (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 with the use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively.Results: Comparisons of presupplementation and postsupplementation ratios indicated that St John's wort significantly induced the activity of CYP2E1 and CYP3A4 (P < .0001). Among female subjects, St John's wort produced significantly greater increases in CYP3A4 phenotypic ratios that appeared to be unrelated to body mass index. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility. Garlic oil reduced CYP2E1 activity by 39% (P = .030), whereas no significant effect on CYP activity was observed for P ginseng and G biloba.Conclusions: Single-time point phenotypic metabolic ratios may provide a practical means of predicting CYP-mediated herb-drug interactions in humans.