Selective Reduction in the Expression of UGTs and SULTs, a Novel Mechanism by which Piperine Enhances the Bioavailability of Curcumin in Rat

Curcumin (CUR) is known to exert numerous health-promoting effects in pharmacological studies, but its low-bioavailability hinders the development of CUR as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of CUR, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which PIP enhances the bioavailability of CUR, dosage ratio (CUR: PIP) and PIP pre-treatment are hypothesized as key factors for bioavailability improvement in this combination. Therefore, combining CUR with PIP at various dose ratio (1:1 to 100:1) and pre-dosing PIP (0.5-8 h prior to CUR) were designed to investigate their contributions to the pharmacokinetic parameters of CUR in rats and their effects on the expression of UGT and SULT isoforms. We showed that Cmax and AUC0-t of CUR were slightly increased by 1.29 and 1.67 folds at the ratio of 20:1, while CUR exposure were significantly enhanced in all PIP pre-treatment rats (0.5-8 h), which peaked at 6 h (6.09-fold and 5.97-fold increase in Cmax and AUC0-t, P < 0.01), regardless of unchanged t1/2 and Tmax. We also observed a time-dependent inhibition on the hepatic expression of UGT1A6, 1A8, SULT1A1, 1A3, and the colonic expression of UGT1A6 that occurred within 6 hours PIP pre-treatment but was reversed at 8 h, which was correlated to the changes of CUR exposure. Similarly, the inhibitory effect of PIP on most of UGTs and SULTs are time-dependent in Caco-2 and HepG2. We conclude that PIP pre-treatment time-dependently improves CUR's bioavailability through reversible and selective inhibition of UGTs and SULTs. This article is protected by copyright. All rights reserved.