Resveratrol glucuronidation in vitro: potential implications of inhibition by probenecid

OBJECTIVES: Resveratrol is a naturally occurring antioxidant with therapeutic potential in prevention and treatment of neoplastic disease and other human disorders. However, net clearance of resveratrol in humans is very high, mainly due to glucuronide conjugation. This leads to extensive presystemic extraction and low plasma concentrations after oral dosage. The present study evaluated the effect of probenecid, an inhibitor of glucuronide conjugation, on resveratrol metabolism in vitro. METHODS: Biotransformation of resveratrol to its 3-O-glucuronide and 4'-O-glucuronide conjugates was studied in vitro using human liver microsomal preparations. The mechanism and inhibitory potency of probenecid were evaluated based on a mixed competitive-noncompetitive inhibition model. KEY FINDINGS: Probenecid inhibition of resveratrol 3-O-glucuronidation was predominantly noncompetitive, with an inhibition constant (Ki ) averaging 3.1 mm. CONCLUSIONS: The ratio of in vivo maximum concentration of probenecid [I] during usual clinical use to the in vitro Ki value ([I]/Ki ) exceeds the boundary value of 0.1, used by regulatory agencies to identify the possibility of clinical drug interactions. This finding, together with the known property of probenecid as an inhibitor of glucuronide conjugation in humans, suggests that probenecid could serve as a pharmacokinetic boosting agent to enhance systemic exposure to resveratrol in humans.