Importance of OATP1B1 and 1B3 in the Liver Uptake of Luteolin and Its Consequent Glucuronidation Metabolites
Hui Zhi, Yuan Yuan, Chunzhen Zhang, Yiguo Jiang, Hongjian Zhang, Cheng Wang, Jianqing Ruan
Abstract
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′-O-glucuronide (L-3′-G) and luteolin-7-O-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.