Intestinal Glucuronidation, Prior to Hepatic Glucuronidation, Plays an Important Role in the Low Circulating Levels of Calycosin

Calycosin is a dietary flavonoid with favorable activities, which seems to be inconsistent with its low circulating levels in vivo. To address this issue, we developed a strategy to understand calycosin distribution by integrating qualitative and quantitative analyses of calycosin and its metabolites in portal vein plasma, the liver, and systemic plasma after oral administration to rats. Consequently, 21 metabolites were characterized in total, including the first report of a reductive biotransformation and 14 new metabolites. Compared with the low levels of calycosin, calycosin glucuronides were predominant in circulation, and both the hepatic and intestinal regions contributed to the high exposure of these calycosin glucuronides. However, intestinal glucuronidation, prior to hepatic glucuronidation, plays a key role in the low circulating levels of calycosin.