Pharmacokinetics and pharmacodynamics of the bioflavonoid biochanin A
Moon, Young Jin
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Breast cancer is the second leading cause of cancer death in women in the U.S. Since the development of breast cancer is primarily influenced by non-genetic factors, environmental conditions such as diet clearly play a significant role in cancer development. Flavonoids are components in a wide range of fruits, vegetables and plant-derived beverages, and have low toxicity. Studies using cells and animals have documented the cancer preventive effects of biochanin A. The overall hypothesis of this dissertation is that the isoflavone biochanin A (BCA) is a breast cancer preventive agent. In vitro cell culture studies have focused on the effect of BCA on the expression of genes at the target site (in mammary cells) and on their effect on drug metabolizing enzymes and membrane transporters (using human hepatocytes). Studies have also characterized the pharmacokinetics of BCA after oral and intravenous administration. We evaluated the hypothesis that multiple flavonoids alter both the pharmacokinetics (PK) and pharmacodynamics (PD) of individual flavonoids and may represent a strategy to increase the bioavailability of individual flavonoids and provide additive or synergistic PD effects. For BCA, we have evaluated the PD effects by determining the effects on cellular proliferation in vitro, and on the chemopreventive effects of BCA in a xenograft murine model of breast cancer. We report, for the first time, changes in the bioavailability of a flavonoid following the administration of multiple flavonoids, and that biochanin A, alone or combined with other flavonoids, is effective in inhibiting tumor growth in a breast cancer animal model.