Pharmacokinetic Interaction Between Oltipraz and Silymarin in Rats
ABSTRACT. Purpose: To evaluate the pharmacokinetic interaction between oltipraz and silymarin after intravenous and oral administration of both drugs to male Sprague–Dawley rats. Methods: Oltipraz (single doses of 10 and 30 mg/kg for intravenous and oral administration, respectively), silymarin (single doses of 50 and 100 mg/kg for intravenous and oral administration, respectively, and 14 days oral administration of 100 mg/kg), alone and together were administered to control rats. Results: The pharmacokinetic parameters of oltipraz did not significantly altered by silymarin. However, after intravenous administration of the drugs together, the AUCs of unconjugated, conjugated, and total (unconjugated plus conjugated) silibinin were significantly different (32.7% decrease, and 32.1% and 27.2% increase, respectively), and total and (CL) and non-renal (CLNR ) clearance of unconjugated silibinin were significantly faster (49.4% and 61.1% increase, respectively) than those of silymarin alone (without oltipraz). After oral administration of silymarin with or without oltipraz, however, the pharmacokinetic parameters of unconjugated, conjugated, and total silibinin were comparable. Conclusions: After single intravenous administration of the drugs together, the AUC of unconjugated silibinin was significantly smaller, but that of both conjugated and total silibinin was significantly greater. This could have been due to an increase in the formation of conjugates (glucuronidation and sulfation) of silibinin as induced by oltipraz. After simultaneous oral administration of the drugs, however, the AUCs (or AUC0−12 h) of unconjugated, conjugated, and total silibinin were comparable.