Importance of OATP1B1 and 1B3 in the Liver Uptake of Luteolin and Its Consequent Glucuronidation Metabolites.

Luteolin is a typical flavonoid and broadly distributed in the plants. Oral bioavailability of luteolin is low owing to extensive metabolism. Regioselective glucuronidation by UDP-glucuronosyltransferases (UGTs) and liver uptake by organic anion transporting polypeptides (OATPs) of luteolin and consequent glucuronidation metabolites were studied. Luteolin-3'--glucuronide (L-3'-G) and luteolin-7--glucuronide (L-7-G) were the major metabolites in human liver microsomes. Further study demonstrated that UGT1A9 played a predominant role in the glucuronidation of luteolin. Transporter study showed that OATP1B1- and 1B3-transfected cells selectively uptake L-3'-G into cells but not luteolin or L-7-G. After intravenous administration of luteolin to mice, the area under the curve of L-3'-G in the plasma was the highest among luteolin, L-3'-G, and L-7-G. In the liver, the concentration of L-3'-G was significantly greater than L-7-G. In conclusion, OATP1B1 and OATP1B3 play an important role in the liver disposition of luteolin and its glucuronidation metabolites.