The present proposal will focus on sequential anaerobic and aerobic metabolism of ginkgo-flavones by intestinal microflora, large intestine, and liver. This sequential metabolism of ginkgo-flavones is expected to be efficient and extensive, because flavonoids and their metabolites are expected to go through repeated enterohepatic recycling. The long-term goal of our study is to determine how this sequential metabolism plus repeated recycling affects the disposition of flavonoids, an important class of antioxidants presented in Ginkgo biloba and many other herbs (e.g., garlic, tea, chamomile, and others). The special focus of the present study is on how bacterial metabolism affects the overall disposition of ginkgo- flavonoids.
The specific aims are to: (l) determine if bacteria will only take up ginkgo-flavones but not ginkgo-flavone glycosides, because of expected poor permeability of glycosides through the bacterial walls; (2) determine the metabolism of each ginkgo-flavone and as a mixture in Ginkgo biloba extract by various groups of bacteria normally residing in human and rat large intestine under anaerobic conditions.; (3) determine how parent compounds and metabolites formed through bacteria metabolism are absorbed in the large intestine,; (4) determine how these metabolites are further metabolized by the large intestine and the liver; and (5) determine how metabolite reshuffling, perhaps for multiple times, into the enterohepatic recycling loop will affect the over metabolic fate of ginkgo flavones and their metabolites. Through these exploratory studies, we would be able to test if a grand recycling scheme which involve sequential metabolism and/or secretion of flavonoids, their microbial and mammalian metabolites, is functionally critical to the disposition of ginkgo-flavonoids. By combining expertise from the two independent disciplines of microbiology and pharmaceutical sciences, we have the capability and the know-how to effectively test this complex hypothesis. if proven, this complex metabolic process will have profound impact on safety and efficacy of this herbal extract and other flavonoid-rich herbal products. Through future animal and human studies in vivo, we would then determine how this grand recycling scheme influences the disposition of a variety of herbal and pharmaceutical products that also undergo, perhaps repeatedly, enterohepatic recycling.
|Chen, Jun; Halls, Steven C; Alfaro, Joshua F et al. (2004) Potential beneficial metabolic interactions between tamoxifen and isoflavones via cytochrome P450-mediated pathways in female rat liver microsomes. Pharm Res 21:2095-104|
|Chen, Jun; Lin, Huimin; Hu, Ming (2003) Metabolism of flavonoids via enteric recycling: role of intestinal disposition. J Pharmacol Exp Ther 304:1228-35|
|Liu, Yong; Liu, Yan; Dai, Yang et al. (2003) Enteric disposition and recycling of flavonoids and ginkgo flavonoids. J Altern Complement Med 9:631-40|
|Hu, Ming; Chen, June; Lin, Huimin (2003) Metabolism of flavonoids via enteric recycling: mechanistic studies of disposition of apigenin in the Caco-2 cell culture model. J Pharmacol Exp Ther 307:314-21|
|Liu, Yan; Hu, Ming (2002) Absorption and metabolism of flavonoids in the caco-2 cell culture model and a perused rat intestinal model. Drug Metab Dispos 30:370-7|