Chainuvati Siwaporn, Nafziger Anne N, Leeder J Steven, Gaedigk Andrea, Kearns Gregory L, Sellers Edward, Zhang Yanhua, Kashuba Angela D M, Rowland Elizabeth, Bertino Joseph S
Department of Medicine, Bassett Healthcare, Cooperstown, NY 13326, USA.
Clin Pharmacol Ther. 2003 Nov;74(5):437-47. doi: 10.1016/S0009-9236(03)00229-7.
Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.
此前，我们已验证了一种4种药物的表型分析鸡尾酒，即“库珀斯敦鸡尾酒”，它包含咖啡因（细胞色素P450 [CYP] 1A2、N - 乙酰转移酶 - 2 [NAT2]和黄嘌呤氧化酶[XO]）、右美沙芬（CYP2D6）、奥美拉唑（CYP2C19）以及静脉注射咪达唑仑（肝脏CYP3A）。数据表明华法林可用作CYP2C9的安全且准确的生物标志物，并且如果华法林与维生素K一同给药，其药效学效应会被消除。12名受试者以随机交叉方式接受了库珀斯敦鸡尾酒、华法林加维生素K以及两组生物标志物（库珀斯敦5 + 1鸡尾酒）。基于对数转换数据和配对t检验，从时间0至无穷大的S - 华法林血清浓度 - 时间曲线下面积（P = 0.09）、奥美拉唑代谢率（P = 0.374）、咖啡因代谢率（CYP1A2活性，P = 0.169）、咪达唑仑血浆清除率（P = 0.573）或右美沙芬代谢率（P = 0.747）在单独使用库珀斯敦鸡尾酒、华法林加维生素K或库珀斯敦5 + 1鸡尾酒时均无显著差异。在给药期间，唯一的副作用是静脉注射咪达唑仑后出现的轻度且短暂的镇静作用。表型测量结果与受试者的CYP2C9、CYP2C19和CYP2D6基因型一致。库珀斯敦5 + 1鸡尾酒可用于同时评估CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A、NAT2和XO的活性。
