Interaction of Organic Anion Transporter 3-Mediated Uptake of Steviol Acyl Glucuronide, a Major Metabolite of Rebaudioside A, with Selected Drugs.

Organic anion transporter 3 (OAT3) plays a critical role in the renal excretion of many xenobiotics. Because steviol acyl glucuronide (SVAG), an OAT3 substrate, is the major circulating metabolite after oral ingestion of steviol glycosides and is excreted into the urine, inhibition of OAT3 activity may alter pharmacokinetic profiles of SVAG. The present study showed that drugs such as probenecid and glimepiride displayed potent inhibition toward the OAT3-mediated SVAG transport, with IC50 values of 4.9 and 0.8 μM, respectively. No species differences were observed. Probenecid and glimepiride could significantly elevate plasma concentrations of SVAG after oral administration of rebaudioside A, with significant increases in plasma maximum (Cmax) and area under the plasma time-concentration curve values. The inhibitory effect on the OAT3-mediated SVAG transport exemplified a unique case between drugs and the metabolite of a food additive. Our data suggest that caution should be exercised when giving steviol glycoside products to human subjects with compromised renal function.