Partovian C, Jacqz-Aigrain E, Keundjian A, Jaillon P, Funck-Brentano C
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
Clin Pharmacol Ther. 1995 Sep;58(3):257-63. doi: 10.1016/0009-9236(95)90241-4.
The main objective of this study was to examine the relations between chloroguanide (proguanil) and mephenytoin metabolic ratios to determine whether or not chloroguanide could replace mephenytoin as a probe for the indirect in vivo measurement of CYP2C19 activity. An additional objective was to examine the interactions between chloroguanide, omeprazole, and mephenytoin, which are three substrates of CYP2C19.
Twenty healthy volunteers received 200 mg chloroguanide orally on three separate occasions in an open, randomized-sequence crossover design: once alone, once 2 hours before the oral administration of 100 mg mephenytoin, and once after oral administration for 7 days of 40 mg/day omeprazole. During one additional period, 100 mg mephenytoin was administered orally. The chloroguanide to cycloguanil ratio was determined in plasma 4 hours after drug administration; it was determined in urine collected over 4, 8, and 24 hours. The mephenytoin hydroxylation index was also measured in urine.
All subjects were extensive metabolizers of chloroguanide and mephenytoin. We found no correlation between the mephenytoin hydroxylation index and the chloroguanide to cycloguanil ratio in any of the urine samples collected or in plasma. In the presence of chloroguanide, mephenytoin hydroxylation index increased from a baseline value of 1.2 +/- 0.2 to 1.7 +/- 1.0 (p < 0.05). In the presence of omeprazole, the chloroguanide to cycloguanil metabolic ratio in 24-hour urine increased from 2.2 +/- 1.0 to 5.6 +/- 3.2 (p < 0.001).
Chloroguanide inhibits the CYP2C19-dependent 4'-hydroxylation of mephenytoin. The bioactivation of chloroguanide to cycloguanil is inhibited by the CYP2C19 substrate omeprazole. However, the chloroguanide to cycloguanil metabolic ratio does not reflect the same array of S-mephenytoin hydroxylase activities found in extensive metabolizers as that show by the mephenytoin hydroxylation index.
本研究的主要目的是检测氯胍（扑疟喹）与美芬妥因代谢率之间的关系，以确定氯胍是否可替代美芬妥因作为体内间接测定CYP2C19活性的探针。另一个目的是检测氯胍、奥美拉唑和美芬妥因之间的相互作用，这三种物质均为CYP2C19的底物。
20名健康志愿者按开放、随机序列交叉设计在三个不同时间口服200mg氯胍：一次单独服用，一次在口服100mg美芬妥因前2小时服用，一次在口服40mg/天奥美拉唑7天后服用。在另外一个时间段，口服100mg美芬妥因。给药4小时后测定血浆中氯胍与环氯胍的比值；在4、8和24小时收集的尿液中进行测定。同时也测定尿液中美芬妥因的羟化指数。
所有受试者都是氯胍和美芬妥因的广泛代谢者。我们发现在所收集的任何尿液样本或血浆中，美芬妥因羟化指数与氯胍与环氯胍的比值之间均无相关性。在氯胍存在的情况下，美芬妥因羟化指数从基线值1.2±0.2增加到1.7±1.0（p<0.05）。在奥美拉唑存在的情况下，24小时尿液中氯胍与环氯胍的代谢率从2.2±1.0增加到5.6±3.2（p<0.001）。
氯胍抑制CYP2C19依赖的美芬妥因4'-羟化反应。CYP2C19底物奥美拉唑抑制氯胍向环氯胍的生物活化。然而，氯胍与环氯胍的代谢率并不能反映广泛代谢者中与美芬妥因羟化指数所显示的相同系列的S-美芬妥因羟化酶活性。
