Comparative toxicokinetics and metabolism of rebaudioside A, stevioside, and steviol in rats

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

“…While the results of the studies of Roberts and Renwick (2008) and Wheeler et al (2008) point to possibly lower systemic exposures to free steviol, or at least lower free steviol relative to steviol glucuronide, in humans compared to the rat (the species from which most toxicology data available), direct comparison of these studies is complicated by the use of different analytical methodologies and resulting different lower limits of quantification, and differences in sample processing. In addition, quantification of the potential magnitude of differences in the toxicokinetics of steviol/steviol glucuronide between rats and humans was not possible because detectable levels of steviol were found in only one human subject at one time point.…”

“…Although steviol glycosides share a common metabolic fate in both rats and humans (Wingard et al, 1980;Hutapea et al, 1997;Gardana et al, 2003;Koyama et al, 2003a;Geuns et al, 2007;Roberts and Renwick, 2008;Wheeler et al, 2008;Nikiforov et al, 2013;Purkayastha et al, 2014Purkayastha et al, , 2015Purkayastha et al, , 2016, some differences in pharmacokinetics have been noted. As evaluated by JECFA at their sixty-ninth meeting (JECFA, 2009), studies comparing the pharmacokinetics of steviol and steviol glucuronide following oral administration of steviol glycosides demonstrated substantial differences in the concentration of circulating plasma steviol and steviol glucuronide between rats and humans (Roberts and Renwick, 2008;Wheeler et al, 2008).…”

“…Once absorbed from the gastrointestinal tract, steviol undergoes conjugation with glucuronic acid in the liver to form steviol glucuronide. In rats, free and conjugated steviol are excreted primarily in the feces via the bile (generally within 48 hours), with smaller amounts appearing in the urine (less than 3%) (Wingard et al, 1980;Roberts and Renwick, 2008). In contrast, elimination of administered steviol glycosides in humans, is primarily in the urine as steviol glucuronide with very small amounts of the unchanged glycoside or steviol (Kraemer and Maurer, 1994;Simonetti et al, 2004;Geuns et al, 2006Geuns et al, , 2007Wheeler et al, 2008).…”

“…Steviol glycosides pass undigested through the upper gastrointestinal tract to the colon where they are hydrolyzed to steviol by sequential removal of one sugar moiety at a time, prior to absorption of steviol (Wingard et al, 1980;Hutapea et al, 1997;Gardana et al, 2003;Koyama et al, 2003a,b;Geuns et al, 2003Geuns et al, , 2007Renwick and Tarka, 2008;Purkayastha et al, 2015). In rats (Roberts and Renwick, 2008), pigs (Geuns et al, 2003) and humans Wheeler et al, 2008) exposures to the parent steviol glycosides are negligible following oral exposure. Once absorbed from the gastrointestinal tract, steviol undergoes conjugation with glucuronic acid in the liver to form steviol glucuronide.…”

“…As evaluated by JECFA at their sixty-ninth meeting (JECFA, 2009), studies comparing the pharmacokinetics of steviol and steviol glucuronide following oral administration of steviol glycosides demonstrated substantial differences in the concentration of circulating plasma steviol and steviol glucuronide between rats and humans (Roberts and Renwick, 2008;Wheeler et al, 2008). Specifically, 4 and 8 h after a single gavage administration of radiolabeled stevioside (4.2 mg/kg bw) to male rats free steviol was detected in the plasma at concentrations of approximately 20 and 18 ng/mL respectively (Roberts and Renwick, 2008). In female rats, concentrations of approximately 40, 46 and 80 ng/mL of steviol were detected at 2, 4 and 8 h post-dose, respectively.…”