Gafni I, Busto U E, Tyndale R F, Kaplan H L, Sellers E M
Institute of Medical Science, dagger Faculty of Pharmacy, double dagger Department of Pharmacology and section sign University of Toronto, Toronto, Canada.
J Clin Psychopharmacol. 2003 Apr;23(2):169-75. doi: 10.1097/00004714-200304000-00009.
Flunitrazepam, a hypnotic benzodiazepine, is widely prescribed around the world for the treatment of insomnia and as a preanesthetic. In vitro studies have shown that the metabolism of flunitrazepam to desmethylflunitrazepam and 3-hydroxyflunitrazepam is mediated in part by the polymorphic enzyme CYP2C19. The objective was to examine the role of CYP2C19 activity in determining flunitrazepam kinetics in vivo. Sixteen healthy volunteers (14 genotypic extensive metabolizers and 2 poor metabolizers) were recruited who had a wide range of CYP2C19 activity (0.50-28.8), as determined by the omeprazole/ 5-hydroxyomeprazole ratio (OMR) at 3 hours following administration of omeprazole, 20 mg orally. Each subject received flunitrazepam, 1 mg orally. Blood samples were collected immediately before and up to 48 hours after drug administration and were assayed by HPLC for flunitrazepam and its metabolites, 7-aminoflunitrazepam, desmethylflunitrazepam, and 3-hydroxyflunitrazepam. Spearman correlations were determined for OMR and pharmacokinetic parameters. With increasing OMR (decreasing CYP2C19 activity), the ratio of flunitrazepam to both desmethylflunitrazepam and 3-hydroxyflunitrazepam AUCs increased ( r = 0.55, p = 0.03 and r = 0.65, p = 0.01, respectively). However, variation in CYP2C19 activity did not significantly affect the AUCs of flunitrazepam or its metabolites. The authors conclude that CYP2C19 contributes to the metabolism of flunitrazepam to desmethylflunitrazepam and 3-hydroxyflunitrazepam in vivo, but these data suggest that its role is minor and that differences in CYP2C19 activity do not likely substantially influence its clinical effects.
氟硝西泮是一种催眠苯二氮䓬类药物，在全球范围内被广泛用于治疗失眠以及作为麻醉前用药。体外研究表明，氟硝西泮代谢为去甲基氟硝西泮和3-羟基氟硝西泮部分是由多态性酶CYP2C19介导的。目的是研究CYP2C19活性在体内氟硝西泮动力学测定中的作用。招募了16名健康志愿者（14名基因型广泛代谢者和2名慢代谢者），他们具有广泛的CYP2C19活性（0.50 - 28.8），这是通过口服20 mg奥美拉唑后3小时的奥美拉唑/5-羟基奥美拉唑比值（OMR）确定的。每位受试者口服1 mg氟硝西泮。在给药前即刻以及给药后长达48小时采集血样，并用高效液相色谱法测定氟硝西泮及其代谢产物7-氨基氟硝西泮、去甲基氟硝西泮和3-羟基氟硝西泮。确定了OMR与药代动力学参数之间的斯皮尔曼相关性。随着OMR增加（CYP2C19活性降低），氟硝西泮与去甲基氟硝西泮和3-羟基氟硝西泮AUCs的比值增加（分别为r = 0.55，p = 0.03和r = 0.65，p = 0.01）。然而，CYP2C19活性的变化并未显著影响氟硝西泮或其代谢产物的AUCs。作者得出结论，CYP2C19在体内参与氟硝西泮代谢为去甲基氟硝西泮和3-羟基氟硝西泮的过程，但这些数据表明其作用较小，CYP2C19活性的差异不太可能对其临床效果产生实质性影响。
