The opportunity for drug-dietary flavonoid interaction is an everyday occurrence whether the interaction is with flavonoids from food, juice, or dietary supplements. This is especially likely when consumption of flavonoids is encouraged for their health benefits. These dietary interactions can be important when total drug absorption is altered. Recently, patents have been filed which incorporate flavonoids as excipients in pharmaceutical formulations with the intent to alter drug absorption characteristics within the intestine. An increase or decrease in drug absorption may be due to (i) alterations in P-glycoprotein (Pgp) mediated or non-Pgp mediated transport and/or (ii) presystemic intestinal metabolism by cytochrome P450 (CYP) and/or the flavin-containing monooxygenases (FMO). Drug metabolism in the small intestine is the initial location of bioconversion of orally administered drugs. Extensive literature exists detailing CYP's role on drug absorption while there is minimal research in the area of FMO intestinal drug metabolism and its effect on drug absorption. The FMO system oxidizes a wide range of pharmaceuticals such as tamoxifen, imipramine, chlorpromazine, clozapine, and albendazole, all of which have low bioavailability. Reports indicate that intestinal FMO is present in rabbits and rats. Recently, FMO-mediated sulfoxidation of cimetidine using human intestinal microsomes is the first study to suggest that FMO is present in the human intestine. To date, there has not been any systematic characterization of intestinal FMO in humans. In humans, flavonoids have been suggested to inhibit FMO activity in vivo and in vitro. The hypothesis of this study is that exposure of humans both to orally administered drugs and dietary flavonoids can alter drug oral bioavailability by influencing presystemic FMO-mediated intestinal drug metabolism. characterization of intestinal FMOs in human duodenum, jejunum, ileum, colon, and in continuous cell lines from intestinal and colonic origin will be investigated. Human intestinal FMOs will be evaluated for the presence of FMO protein and FMO catalytic activity. Also, direct inhibitory or stimulatory effects of flavonoids on the metabolism of methimazole, cimetidine, and N-deacetyl ketoconazole will be evaluated using cDNA-expressed human FMOs. Thus, this project will contribute to the knowledge of human intestinal metabolism as well as provide an understanding of the effect of dietary flavonoids on intestinal FMO-mediated metabolism of orally administered therapeutic drugs within the various regions of the digestive tract.
