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Baicalein is a dietary flavonoid that exhibits a variety of intestinal pharmacological activities with limited oral bioavailability. In the present study, the intestinal pharmacokinetics of baicalein was determined by HPLC-ESI-MS/MS and HPLC-PDA analysis. After oral administration, the intestinal concentration of baicalein was peaked at 1 h, and the amount of baicalein in the intestine corresponded to 87%, 45%, and 20% of the administered dose at 1 h, 8 h, and 12 h, respectively. Glucuronidation, sulfation, and methylation metabolites were the major metabolites of baicalein in the small intestine, including duodenum, jejunum, and ileum. Dehydroxylation, sulfation, and methylation metabolites were the major metabolites in the large intestine, including cecum and colon. In vitro, baicalein was transformed into its glucuronidation and methylation metabolites in hepatic and intestinal S9 fraction. The glucuronidation metabolites was hydrolyzed to baicalein by gut microbiota, but the dehydroxylation and methylation metabolites were stable during gut microbiota incubation.In conclusion, the intestinal concentration of baicalein can support its intestinal pharmacological activities, and the present study may provide useful information for understanding the bioactivities of flavonoids with limited systemic bioavailability.

Graphic abstract Highlights • Baicalein was found to be abundant in the intestine after oral administration. • The amount of baicalein can support its intestinal pharmacological activities. • Baicalein metabolites were of different compositions in different intestinal tissues. • Phase II metabolites of baicalein were the major metabolites in the small intestine. • Metabolites produced by gut microbiota were of high abundance in the large intestine. Abstract Baicalein is a dietary flavonoid that exhibits a variety of intestinal pharmacological activities with limited oral bioavailability. In the present study, the intestinal pharmacokinetics of baicalein was determined by HPLC-ESI-MS/MS and HPLC-PDA analysis. After oral administration, the intestinal concentration of baicalein was peaked at 1 h, and the amount of baicalein in the intestine corresponded to 87%, 45%, and 20% of the administered dose at 1 h, 8 h, and 12 h, respectively. Glucuronidation, sulfation, and methylation metabolites were the major metabolites of baicalein in the small intestine, including duodenum, jejunum, and ileum. Dehydroxylation, sulfation, and methylation metabolites were the major metabolites in the large intestine, including cecum and colon. In vitro , baicalein was transformed into its glucuronidation and methylation metabolites in hepatic and intestinal S9 fraction. The glucuronidation metabolites was hydrolyzed to baicalein by gut microbiota, but the dehydroxylation and methylation metabolites were stable during gut microbiota incubation. In conclusion, the intestinal concentration of baicalein can support its intestinal pharmacological activities, and the present study may provide useful information for understanding the bioactivities of flavonoids with limited systemic bioavailability. [ABSTRACT FROM AUTHOR]

The present investigation addressed the role of verapamil for oral pharmacokinetics of morphine-6-β-glucuronide (M6G). Male Sprague–Dawley rats received 62.5 mg kg−1 M6G-dihydrate orally w/wo pre-treatment with 70 mg kg−1 verapamil. Intravenous M6G (3.9 mg kg−1 ) and oral morphine (52.7 mg kg−1 morphine–hydrochloride) were also employed. Oral bioavailability of M6G and the fraction of M6G deglucuronidated to morphine were estimated from areas under the plasma-concentration vs. time curves (AUC) of morphine and its glucuronides. As initial results pointed towards inhibition of glucuronidases by verapamil, its capability to specifically inhibit E. coli and/or rat intestinal β-glucuronidase was assessed using altered cleavage of the model substrate 4-methylumbelliferyl-β-d-glucuronide (MUG). Oral bioavailability of M6G was 2.1%; 13% of oral M6G was deglucuronidated to morphine. Co-administration of verapamil did not increase the AUC of M6G. AUCs of morphine and morphine-3-glucuronide were smaller in the verapamil group than in controls. Verapamil co-administration decreased the fraction of M6G deglucuronidated to morphine to 4.6%. In vitro experiments provided evidence that verapamil inhibits β-glucuronidase from E. coli with an ic50 of 30 μM, whereas no inhibition of the rat β-glucuronidase from small intestine was seen. In conclusion, verapamil decreased intestinal deglucuronidation of M6G by inhibiting E. coli β-glucuronidase. This indicates that verapamil is not suited as P-gp inhibitor in experiments involving glucuronides. An increase in the intestinal absorption of M6G due to P-gp-inhibition was not observed at the verapamil dose studied. [Copyright &y& Elsevier]