氟西汀对美沙酮在大鼠体内药物动力学的影响

Effect of Fluoxetine on Methadone Pharmacokinetics in Rats

目的:研究氟西汀在大鼠体内对美沙酮药物动力学的影响。方法:16只Sprague Dawley雄性大鼠随机分成对照组和实验组,对照组灌胃给予盐酸美沙酮6 mg·kg^-1,实验组同时灌胃给予盐酸美沙酮6 mg·kg^-1和盐酸氟西汀10 mg·kg^-1。采用超高效液相-质谱联用(UPLC-MS/MS)方法测定大鼠血浆中美沙酮及其代谢产物2-亚乙基^-1,5-二甲基-3,3-二苯基吡咯烷(EDDP)的血药浓度并进行药物动力学分析。结果:合用氟西汀后,美沙酮的AUC增加了3.95倍,半衰期增加了2.48倍,峰浓度增加了2.24倍,清除率下降了77.25%;EDDP的AUC增加了3.75倍,达峰时间延长了2.80倍,清除率下降了75.51%。结论:氟西汀可使美沙酮及其代谢产物在大鼠体内的药物动力学显著变化。临床上进行美沙酮维持治疗的患者合用氟西汀时,需注意美沙酮不良反应的监测以及剂量的调整。

Objective:To observe the effect of fluoxetine on methadone pharmacokinetics in rats.Methods:Totally 16 male Sprague Dawley rats were divided into the control group and the experimental group.The control group was administrated with 6 mg·kg^-1 methadone and the experimental group was co-administrated with 6 mg·kg^-1 methadone and 10 mg·kg^-1 fluoxetine.The drug concentrations of methadone and its metabolite,2-ethylidene^-1,5-dimethyl-3,3-diphenylpyrrolidine(EDDP)in rat’s plasma were determined by an ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method and pharmacokinetics was analyzed subsequently.Results:When co-administrated with fluoxetine,the AUC,half-life and Cmaxof methadone were increased by3.95-fold,2.48-fold and 2.24-fold,respectively,and the clearance was decreased by 77.25%.The AUC and Tmaxof EDDP were increased by 3.75-fold and 2.80-fold,respectively,and the clearance was decreased by 75.51%.Conclusion:Fluoxetine significantly affect methadone’s pharmacokinetics in rats.Monitoring of side effects and dose adjustment should be paid attention in individuals undergoing methadone maintenance therapy when fluoxetine is concomitant.