Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole

A clinical study was undertaken in 12 healthy volunteers. At first, subjects received metronidazole (CAS 443-48-1; a substrate for cytochrome CYP3A4 and CYP2C9) alone at a dose of 400 mg every 8 h for 3 days. On day 4, blood and urine were collected at different time points and metronidazole levels were measured. After a washout period (> 10 half-lives) of one week silymarin (CAS 22888-70-6) was given at a daily dose of 140 mg for 9 days. From day 7 both silymarin (140 mg/day) and metronidazole (3 x 400 mg/ day) were given till the 9(th) day. On day 10, blood and urine were collected as above and the levels of metronidazole and its metabolite were measured by HPLC. Administration of silymarin increased the clearence of metronidazole and its major metabolite, hydroxy-metronidazole (HM) by 29.51% and 31.90%, respectively, with a concomitant decrease in half-life, C-max and AUC(0-48). Urinary excretions of acid-metronidazole (AM), HM as well as metronidazole in 48 h were decreased. The results indicate that silymarin might induce both intestinal P-glycoprotein and CYP3A4 upon multiple dose administration.