Silibinin affects the pharmacokinetics of methadone in rats

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 100mg/kg group, multiple doses of 100mg/kg group, and multiple doses of 30mg/kg group. A single dose of 6mg/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 100mg/kg silibinin significantly increased the C-max of methadone, but only 100mg/kg silibinin significantly increased the AUC((0-t)) of methadone and decreased its clearance. Pharmacokinetics parameters of EDDP were not altered by 30mg/kg silibinin; its T-max was decreased by 100mg/kg silibinin and the C-max was increased by single dose of 100mg/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.