Dramatic increase in hepatic and biliary curcumin exposure by modulation of its elimination pathway in rats

Abstract

Curcumin, a major component of the food spice turmeric (Curcuma longa), has multiple beneficial effects on diseases of the liver and bile duct. We have investigated whether modulation of the curcumin elimination pathway could increase its hepatic and biliary exposure in rats. Probenecid, an inhibitor of the metabolism and biliary excretion of curcumin, was used as a modulator. After intravenous administration of curcumin at a dose of 18 mg/kg/h without (control) or with co-infusion of probenecid (230 mg/kg/h) in rats, the pharmacokinetic parameters of curcumin were estimated. Coadministration of probenecid significantly increased the total area under the plasma (1.88-fold) and bile (6.73-fold) concentration-time curves from 0 to 80 min of curcumin relative to those in the controls. The tissue-to-plasma concentration ratio in the liver was also dramatically increased (69.3-fold) by probenecid. These results may be attributed to the dual inhibitory effects of probenecid, to a greater extent, on metabolism via glucuronidation, and to a lesser extent, on the biliary excretion of curcumin via the multidrug resistance-associated protein 2. The probenecid-mediated increase in hepatic and biliary exposure of curcumin suggested that the use of combination drug regimens involving curcumin and modulators of elimination may be an innovative approach for the therapeutic use of curcumin.