Perucca E, Gatti G, Cipolla G, Spina E, Barel S, Soback S, Gips M, Bialer M
Department of Internal Medicine and Therapeutics, University of Pavia, Italy.
Clin Pharmacol Ther. 1994 Nov;56(5):471-6. doi: 10.1038/clpt.1994.167.
The effect of fluvoxamine on the pharmacokinetics of diazepam and metabolically derived N-desmethyl-diazepam was investigated in eight healthy volunteers. Each subject received a single oral dose of diazepam (10 mg) in a control session and on the fourth day of a 16-day treatment with fluvoxamine maleate (100 to 150 mg daily). Compared with the control session, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/ml, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (from 0.40 to 0.14 ml/min/kg; p < 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p < 0.01). Although peak plasma N-desmethyldiazepam levels were similar in the two sessions, the time required for the metabolite to reach a peak was longer during fluvoxamine intake than in the control session (206 versus 62 hours; p < 0.01). N-Desmethyldiazepam area under the plasma concentration-time curve values were also significantly increased during fluvoxamine treatment. These data suggest that fluvoxamine inhibits the biotransformation of diazepam and its active N-demethylated metabolite. The magnitude of this interaction is likely to have considerable clinical significance.
在8名健康志愿者中研究了氟伏沙明对地西泮及其代谢产物N-去甲基地西泮药代动力学的影响。每位受试者在对照期接受单次口服地西泮（10mg），并在接受马来酸氟伏沙明（每日100至150mg）治疗16天的第4天再次接受该剂量。与对照期相比，同时服用氟伏沙明会使地西泮的平均血浆峰浓度升高（从108ng/ml升至143ng/ml，几何平均数，差异无统计学意义），明显降低地西泮的表观口服清除率（从0.40ml/min/kg降至0.14ml/min/kg；p<0.01），并延长地西泮的半衰期（从51小时延长至118小时；p<0.01）。虽然两期血浆中N-去甲基地西泮的峰浓度相似，但在服用氟伏沙明期间，该代谢产物达到峰值所需的时间比对照期更长（206小时对62小时；p<0.01）。在氟伏沙明治疗期间，N-去甲基地西泮的血浆浓度-时间曲线下面积值也显著增加。这些数据表明，氟伏沙明抑制地西泮及其活性N-去甲基代谢产物的生物转化。这种相互作用的程度可能具有相当大的临床意义。
