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Vol. 30, Issue 4, 370-377, April 2002
Department of Pharmaceutical Sciences, College of Pharmacy,
Washington State University, Pullman, Washington
The purpose of present study was to determine the intestinal
absorption and metabolism of genistein and its analogs to better understand the mechanisms responsible for their low oral
bioavailability. The Caco-2 cell culture model and a perfused rat
intestinal model were used for the study. In both models,
permeabilities of aglycones (e.g., genistein) were comparable to well
absorbed compounds, such as testosterone and propranolol. In the Caco-2
model, permeabilities of aglycones were at least 5 times higher
(p < 0.05) than their corresponding glycosides
(e.g., genistin), and the vectorial transport of aglycones was similar
(p > 0.05). In contrast, vectorial transport of
glucosides favored excretion (p < 0.05). Limited
hydrolysis of glycosides was observed in the Caco-2 model, which was
completely inhibited (p < 0.05) by 20 mM
gluconolactone, a broad specificity glycosidase inhibitor. In the
perfused rat intestinal model, genistin was rapidly hydrolyzed (about
40% in 15 min) in the upper intestine but was not hydrolyzed at all in
the colon. Aglycones were rapidly absorbed
(P*eff > 1.5), and absorbed aglycones
underwent extensive (40% maximum) phase II metabolism via
glucuronidation and sulfation in the upper small intestine. Similar to
the hydrolysis, recovery of conjugated genistein was also
region-dependent, with jejunum having the highest and colon the lowest
(p < 0.05). This difference in conjugate recovery
could be due to the difference in the activities of enzymes or efflux
transporters, and the results of studies tend to suggest that both of
these factors were involved. In conclusion, genistein and its analogs
are well absorbed in both intestinal models, and therefore, poor
absorption is not the reason for its low bioavailability. On the other
hand, extensive phase II metabolism in the intestine significantly
contributes to its low bioavailability.
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