Effects of estrogen and estrus cycle on pharmacokinetics, absorption, and disposition of genistein in female Sprague-Dawley rats.

Genistein is an active soy isoflavone with anticancer activities, but it is unknown why it has a higher oral bioavailability in female than in male rats. Our study determined the effects of estrus cycle on genistein's oral bioavailability. Female rats with various levels of estrogen were orally administered with genistein or used in a four-site rat intestinal perfusion experiment. Rats in "proestrus" group (with elevated estrogen) had significantly reduced (57% decrease, p < 0.05) oral bioavailability of total genistein (aglycone + conjugates) than those in "metoestrus" group (with basal level of estrogen). Female ovariectomized rats, due to lack of estrogen, showed oral bioavailability of total genistein similar to the "metoestrus" group but higher (155% increase, p < 0.05) than the "proestrus" group. On the basis of intestinal perfusion studies, the increased bioavailability was partially attributed to the higher (>100% increase, p < 0.05) hepatic disposition via glucuronidation and possibly more efficient enterohepatic recycling of genistein in the "metoestrus" group. Furthermore, chronic exogenous supplementation of estradiol in ovariectomized rats significantly reduced (77%, p < 0.05) the oral bioavailability of total genistein, mostly via increased sulfation (>10-fold) in liver, to a level comparable to those in the "proestrus" group. In conclusion, the oral bioavailability of total genistein was inversely proportional to elevated estrogen levels in female rats, which is partially mediated through the regulation of hepatic enzymes responsible disposition of genistein.