Dietary flavonoids exert a broad range of biological effects including anticancer, antioxidant, antiosteoperosis, cholesterol lowering, and anti-aging, which make them attractive for preventing cancer and cardiovascular ailments and for impeding the progress of degenerative diseases. However, these compounds are poorly bioavailable, which impedes their development as viable drugs. The long-term goal of our study is to determine how efflux transporters of hydrophilic phase II conjugates control the overall disposition of flavonoids and determine their biological fate in vivo. The central hypothesis for the present research proposal is that the local and systemic bioavailability of a flavonoid will be improved by modulating the function of a critical efflux transporter responsible for its distributin to the local target organs (e.g., colon) or the systemic circulation. Our central hypothesis is a step beyond the classical hypothesis that bioavailabilities of drugs can only be improved if more are absorbed and/or less of the absorbed amount is metabolized.
The Specific Aims of this renewal proposal are to: (1) construct precise quantitative cellular metabolic models to describe the kinetics of glucuronide formation and efflux at the molecular level;(2) determine the quantitative structure-efflux relationships (QSERs) for three key efflux transporters of flavonoid glucuronides: BCRP, MRP2, and MRP3;and (3) establish a glucuronidation classification system to map which flavonoid is likely to have good bioavailability by manipulating a particular efflux transporter. Successful completion of our research project will significantly advance the basic sciences as well as practical knowledge that may be used to improve the bioavailability of flavonoids and relevant drugs for human health.
Dietary flavonoids exert a broad range of biological effects including anticancer, antioxidant, antiosteoperosis, cholesterol lowering, and anti-aging, which make them attractive for preventing cancer and cardiovascular ailments and for impeding the progress of degenerative diseases. However, these compounds are poorly bioavailable, which impedes their development as viable drugs. The proposed study will identify means to improve the bioavailability of flavonoids and enhance the chance that flavonoids could be successfully developed into drugs. It is expected that significant advances achieved through this research are applicable to the development of other drugs with similar delivery challenges so we can develop more drugs for humans at an accelerated pace.
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