Time-Dependent Metabolism of Luteolin by Human UDP-Glucuronosyltransferases and Its Intestinal First-Pass Glucuronidation in Mice

Luteolin is a well-known flavonoid with various pharmacological properties but has low bioavailability due to glucuronidation. This study investigated the time-course of luteolin glucuronidation by 12 human UDP-glucuronosyltransferases (UGTs) and its intestinal first-pass metabolism in mice. Six metabolites, including two novel abundant diglucuronides [3′,7-O-diglucuronide (diG) and 4′,7-diG] and four known ones, were identified. UGT1A6 and UGT1A9 generated almost only monoglucuronides (G’s). The production of 3′,7-diG followed a sequential time-dependent process along with decrease of 3′-G mainly by UGT1A1, indicating that 3′,7-diG was produced from 3′-G. Metabolism in mice intestine differed from that in humans. Probenecid, a nonspecific UGT inhibitor, did not affect absorption but significantly inhibited production of 7-, 4′-, and 3′-G, and enhanced the formation of another novel metabolite, 5-G, in mice. In conclusion, diglucuronide formation is time-dependent and isoform-specific. UGT1A1 preferentially generates diG, whereas UGT1A6 and UGT1A9 share a preference for G production.