Pan Pei-Pei, Wang Jun, Luo Jun, Wang Shuang-Hu, Zhou Yun-Fang, Chen Sai-Zhen, Du Zhou
Department of Pharmacy, Taizhou Central Hospital, Taizhou, Zhejiang, PR China.
Department of Pharmacy, The Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital, Wenzhou, Zhejiang, PR_China.
Drug Test Anal. 2018 Mar;10(3):557-561. doi: 10.1002/dta.2235. Epub 2017 Aug 24.
The aim of the present study was to investigate the pharmacokinetic effect of silibinin on methadone in rats. Twenty-four male Sprague-Dawley rats were randomly divided into 4 groups: control group, single dose of 100 mg/kg group, multiple doses of 100 mg/kg group, and multiple doses of 30 mg/kg group. A single dose of 6 mg/kg methadone was administrated to rats orally without or with silibinin. Plasma samples were collected via tail vein at different time points and concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), were determined by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Compared with the control group (without silibinin), both 30 and 100 mg/kg silibinin significantly increased the C of methadone, but only 100 mg/kg silibinin significantly increased the AUC of methadone and decreased its clearance. Pharmacokinetics parameters of EDDP were not altered by 30 mg/kg silibinin; its T was decreased by 100 mg/kg silibinin and the C was increased by single dose of 100 mg/kg silibinin. It is concluded that silibinin significantly altered the pharmacokinetics of methadone in rats by increasing the exposure of methadone. Further investigations in human should be conducted. Therapeutic drug monitoring of methadone in individuals undergoing methadone maintenance therapy is recommended when silibinin is concomitant.
本研究的目的是调查水飞蓟宾对大鼠体内美沙酮药代动力学的影响。将24只雄性Sprague-Dawley大鼠随机分为4组：对照组、单剂量100 mg/kg组、多剂量100 mg/kg组和多剂量30 mg/kg组。给大鼠口服单剂量6 mg/kg美沙酮，同时或不同时给予水飞蓟宾。在不同时间点通过尾静脉采集血浆样本，采用超高效液相色谱-串联质谱法（UPLC-MS/MS）测定美沙酮及其代谢物2-亚乙基-1,5-二甲基-3,3-二苯基吡咯烷（EDDP）的浓度。与对照组（未给水飞蓟宾）相比，30和100 mg/kg水飞蓟宾均显著提高了美沙酮的Cmax，但只有100 mg/kg水飞蓟宾显著提高了美沙酮的AUC并降低了其清除率。30 mg/kg水飞蓟宾未改变EDDP的药代动力学参数；100 mg/kg水飞蓟宾降低了EDDP的Tmax，单剂量100 mg/kg水飞蓟宾提高了其Cmax。结论是水飞蓟宾通过增加美沙酮的暴露量显著改变了大鼠体内美沙酮的药代动力学。应在人体中进行进一步研究。当同时使用水飞蓟宾时，建议对接受美沙酮维持治疗的个体进行美沙酮治疗药物监测。
