Received for publication January 25, 2005.
Revised August 23, 2005.
Accepted for publication August 23, 2005.

Disposition of Flavonoids via Recycling: Comparison of Intestinal versus Hepatic Disposition

Abstract

The purpose of this study was to compare intestinal versus hepatic disposition of six flavonoids in order to fully characterize their first-pass metabolism. The perfused rat intestinal model and microsomes prepared from rat liver, duodenum, jejunum, ileum and colon were used. The results indicated that isoflavone (12.5 µM) glucuronidation was highly variable among different microsomes prepared from liver or intestine. Comparing to liver metabolism, the intestinal metabolism had higher K_m values (>2 folds). Likewise, the hepatic intrinsic clearance (IC, or a ratio of V_max/K_m) values of isoflavones were generally higher than their intestinal IC values (200%-2000% higher), except for prunetin, whose jejunal IC value was 50% higher than its hepatic IC. When comparing intestinal metabolism, the results showed that intestinal metabolism rates and V_max values of isoflavones were less when an additional A-ring electron-donating group was absent (i.e., daidzein and formononetin). In rat perfusion model using the whole small intestine, genistein (10 µM) was well absorbed (77% or 352 nmol/120 min). The first-pass metabolism of genistein was extensive, with 40% of absorbed genistein excreted as conjugated metabolites into the intestinal lumen. In contrast, the bile excretion of genistein conjugates was much less (6.4% of absorbed genistein). In conclusion, intestinal glucuronidation is slower in isoflavones without an additional A-ring substitution. Perfusion studies suggest that intestine is the main organ for genistein glucuronide formation and excretion in rats, and may serve as its main first-pass metabolism organ.

Key words: absorption, enzyme kinetics, excretion, in vitro-in vivo prediction, intestinal transport, phase II drug metabolism, structure-activity relationships, UDP glucuronyltransferases

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