Interactions of resveratrol and its metabolites (resveratrol-3-sulfate, resveratrol-3-glucuronide, and dihydroresveratrol) with serum albumin, cytochrome P450 enzymes, and OATP transporters.

Resveratrol (RES) is a widely-known natural polyphenol which is also contained by several dietary supplements. Large doses of RES can result in high micromolar levels of its sulfate and glucuronide conjugates in the circulation, due to the high presystemic metabolism of the parent polyphenol. Pharmacokinetic interactions of RES have been extensively studied, while only limited data are available regarding its metabolites. Therefore, in the current study, we examined the interactions of resveratrol-3-sulfate (R3S), resveratrol-3-glucuronide, and dihydroresveratrol (DHR; a metabolite produced by the colon microbiota) with human serum albumin (HSA), cytochrome P450 (CYP) enzymes, and organic anion transporting polypeptides (OATP) employing in vitro models. Our results demonstrated that R3S and R3G may play a major role in the RES-induced pharmacokinetic interactions: (1) R3S can strongly displace the site I marker warfarin from HSA; (2) R3G showed similarly strong inhibitory action on CYP3A4 to RES; (3) R3S proved to be similarly strong (OATP1B1/3) or even stronger (OATP1A2 and OATP2B1) inhibitor of OATPs tested than RES, while R3G and RES showed comparable inhibitory actions on OATP2B1.