Lamberg T S, Kivistö K T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki, Finland.
Clin Pharmacol Ther. 1998 Jun;63(6):640-5. doi: 10.1016/S0009-9236(98)90087-X.
Buspirone has an extensive first-pass metabolism, which makes it potentially susceptible to drug interactions. The aim of this study was to investigate possible interactions of buspirone with verapamil and diltiazem.
In a randomized, placebo-controlled, three-phase crossover study, nine healthy volunteers received either 80 mg verapamil, 60 mg diltiazem, or placebo orally three times a day. On day 2, after the fifth dose, 10 mg buspirone was given orally. Plasma concentrations of buspirone, verapamil, and diltiazem were determined up to 18 hours, and the effects of buspirone were measured up to 8 hours.
Verapamil and diltiazem increased the area under the buspirone plasma concentration-time curve [AUC (0-infinity)] 3.4-fold (p < 0.001) and 5.5-fold (p < 0.001), respectively. The peak plasma concentration of buspirone was increased 3.4-fold (p < 0.001) and 4.1-fold (p < 0.001) by verapamil and diltiazem, respectively. The effect of diltiazem on the AUC(0-infinity) of buspirone was significantly (p < 0.05) greater than that of verapamil. The elimination half-life of buspirone was not changed by verapamil and diltiazem. Of the six pharmacodynamic variables, only the subjective overall drug effect of buspirone was significantly increased with verapamil (p < 0.05) and diltiazem (p < 0.05). Side effects of buspirone occurred more often (p < 0.05) with diltiazem than with placebo.
Both verapamil and diltiazem considerably increase plasma buspirone concentrations, probably by inhibiting its CYP3A4-mediated first-pass metabolism. Thus enhanced effects and side effects of buspirone are possible when it is used with verapamil, diltiazem, or other inhibitors of CYP3A4.
丁螺环酮具有广泛的首过代谢，这使其可能易发生药物相互作用。本研究的目的是调查丁螺环酮与维拉帕米和地尔硫䓬之间可能的相互作用。
在一项随机、安慰剂对照、三阶段交叉研究中，9名健康志愿者每天口服3次80毫克维拉帕米、60毫克地尔硫䓬或安慰剂。在第2天，第5剂给药后，口服10毫克丁螺环酮。测定丁螺环酮、维拉帕米和地尔硫䓬的血浆浓度长达18小时，并测定丁螺环酮的效应长达8小时。
维拉帕米和地尔硫䓬分别使丁螺环酮血浆浓度-时间曲线下面积[AUC(0-∞)]增加3.4倍（p<0.001）和5.5倍（p<0.001）。维拉帕米和地尔硫䓬分别使丁螺环酮的血浆峰浓度增加3.4倍（p<0.001）和4.1倍（p<0.001）。地尔硫䓬对丁螺环酮AUC(0-∞)的影响显著（p<0.05）大于维拉帕米。维拉帕米和地尔硫䓬未改变丁螺环酮的消除半衰期。在6个药效学变量中，只有丁螺环酮的主观总体药物效应在与维拉帕米（p<0.05）和地尔硫䓬（p<0.05）合用时显著增加。地尔硫䓬组丁螺环酮的副作用发生率高于安慰剂组（p<0.05）。
维拉帕米和地尔硫䓬均显著增加丁螺环酮的血浆浓度，可能是通过抑制其CYP3A4介导的首过代谢。因此，当丁螺环酮与维拉帕米、地尔硫䓬或其他CYP3A4抑制剂合用时，丁螺环酮的效应和副作用可能会增强。
