Silymarin‐mediated Natural Product–Drug Interactions involving Enteric Organic Anion Transporting Polypeptides

Abstract

Organic anion transporting polypeptides (OATPs in humans; Oatps in rodents) represent a large family of uptake transporters important to drug disposition. Several factors can disrupt transport activity of OATPs/Oatps, including inhibition by natural products found in the diet and in dietary supplements. Silymarin, an extract of Silybum marianum (L.) Gaertn. seeds, is a widely consumed dietary supplement for hepatobiliary disorders that is reported to inhibit OATPs/Oatps. Although there is potential for high intestinal concentrations of flavonolignans after oral consumption, very little research has explored the risk of an enteric interactions between silymarin and OATP/Oatp substrates. Therefore, we hypothesize that clinically relevant doses of silymarin will inhibit enteric OATP/Oatp activity and pose a risk for decreased systemic drug concentrations. IC­50 data for the individual flavonolignans were collected using cells overexpressing OATPs. OATP2B1, the major OATP expressed in human enterocytes, was inhibited by silymarin (IC50: 3.9 µM). Further analysis of individual flavonolignans, which are the major constituents in silymarin revealed IC50 values below 10 µM (isosilybin A: 2.7 µM, isosilybin B: 9.4 µM, silychristin: 8.2 µM, silydianin: 5.5 µM). FDA guidance provides metrics for predicting the risk of an intestinal in vivo interaction from in vitro data (R value ≥ 11) based on the proportionality between the maximal extracellular inhibitor concentration and the IC50 data. For flavonolignans from silymarin, maximal intestinal concentrations are estimated to be considerably greater than the experimentally derived IC50 data. Consequently, silymarin doses as low as 140 mg produced R values for flavonolignans that exceeded the FDA threshold. These data suggest enteric OATPs/Oatps may be susceptible to silymarin‐mediated inhibition and potentially decrease systemic drug concentrations.