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

Abstract

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 IC 50 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 (C max ) and area under the plasma time−concentration curve values. The inhibitory effect on the OAT3mediated 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.

Effects of Probenecid on Hepatic and Renal Disposition of Hexadecanedioate, an Endogenous Substrate of Organic Anion Transporting Polypeptide 1B in Rats

“…Regarding the elimination pathway for HDA, hepatic metabolism could provide a major contribution to the body. First, approximately 55% of the administered dose of d-HDA was recovered in the liver at 5 min, which agrees with previous observations that 35 S-labeled 2-mercapto-1,16-HDA is predominantly distributed in the liver rather than in the kidney. 38 Endogenous HDA has been suggested to be synthesized by the u-oxidation of palmitic acid, 39,40 and the enzymes involved have been characterized in various organs, including the liver, brain, lung, and kidney.…”

Identification of Structural Features for the Inhibition of OAT3-Mediated Uptake of Enalaprilat by Selected Drugs and Flavonoids

“…Many OAT3 substrates with high K m values have demonstrated in vivo interactions due to inhibition. Those substrates include but not limited to steviol acyl glucuronide with K m of 368.1 µM (Zhou et al, 2020), mesna with K m of 390 µM (Cutler et al, 2012), and isoniazid with K m of 233.7 µM (Parvez et al, 2018). Judging from quantitative proteomic data, both OAT3 and OAT1 are highly and equally expressed in human kidney, whereas OATPs are below detection limits (Prasad et al, 2016;Uchida et al, 2016).…”

“…A human pharmacokinetic study indicated that probenecid could markedly increase systemic exposure of enalapril and enalaprilat by decreasing their renal excretion (Noormohamed et al, 1990). As probenecid is a well characterized inhibitor of OAT3 (Tahara et al, 2006;Zhou et al, 2020), it could be assumed that the interaction between probenecid and enalapril/enalaprilat might be associated with OAT3-mediated renal clearance, although no direct evidence on OAT3's involvement was described.…”

Recent Advances in Synthetic Drugs and Natural Actives Interacting with OAT3

“…The AUC 6–8h of steviol acyl glucuronide was increased to 2.9- or 2.5-fold, respectively. Therefore, people with impaired renal function should be cautious when taking steviol glycoside products [ 59 ].…”