Disposition of flavonoids via recycling: Direct biliary excretion of enterically or extrahepatically derived flavonoid glucuronides.

Abstract

SCOPE: Enterohepatic recycling is often thought to involve mostly phase II metabolites generated in the liver. This study aims to determine if direct biliary excretion of extrahepatically generated glucuronides would also enable recycling. METHODS AND RESULTS: Conventional and modified intestinal perfusion models along with intestinal and liver microsomes were used to determine the contribution of extrahepatically derived glucuronides. Glucuronidation of four flavonoids (genistein, biochanin A, apigenin, and chrysin at 2.5-20&#xa0;&#x3bc;M) were generally more rapid in the hepatic than intestinal microsomes. Furthermore, when aglycones (at 10&#xa0;&#x3bc;M each) were perfused, larger (1.7-9 fold) amounts of glucuronides were found in the bile than in the luminal perfusate. However, higher concentrations of glucuronides were not found in jugular vein than portal vein, and apigenin glucuronide actually displayed a significantly lower concentration in jugular vein (<1 nM) than portal vein (&#x2248;4 nM). A direct portal infusion of four flavonoid glucuronides (5.9-10.4&#xa0;&#x3bc;M perfused at 2 mL/h) showed that the vast majority (>65%) of the glucuronides (except for biochanin A glucuronide) administered were efficiently excreted into the bile. CONCLUSION: Direct biliary excretion of extrahepatically generated flavonoid glucuronides is a highly efficient clearance mechanism, which should enable enterohepatic recycling of flavonoids without hepatic conjugating enzymes.