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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM070737-07A1
Application #
8697807
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Okita, Richard T
Project Start
2006-06-05
Project End
2018-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Houston
Department
Type
Schools of Pharmacy
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77204
Wang, Liping; Chen, Qingwei; Zhu, Lijun et al. (2017) Metabolic Disposition of Luteolin Is Mediated by the Interplay of UDP-Glucuronosyltransferases and Catechol-O-Methyltransferases in Rats. Drug Metab Dispos 45:306-315
Chaudhari, Rajan; Tan, Zhi; Huang, Beibei et al. (2017) Computational polypharmacology: a new paradigm for drug discovery. Expert Opin Drug Discov 12:279-291
Ge, Shufan; Yin, Taijun; Xu, Beibei et al. (2016) Curcumin Affects Phase II Disposition of Resveratrol Through Inhibiting Efflux Transporters MRP2 and BCRP. Pharm Res 33:590-602
Zheng, Liang; Zhu, Lijun; Zhao, Min et al. (2016) In Vivo Exposure of Kaempferol Is Driven by Phase II Metabolic Enzymes and Efflux Transporters. AAPS J 18:1289-99
Wang, Meifang; Yang, Guangyi; He, Yu et al. (2016) Establishment and use of new MDCK II cells overexpressing both UGT1A1 and MRP2 to characterize flavonoid metabolism via the glucuronidation pathway. Mol Nutr Food Res 60:1967-83
Basu, Sumit; Zeng, Min; Yin, Taijun et al. (2016) Development and validation of an UPLC-MS/MS method for the quantification of irinotecan, SN-38 and SN-38 glucuronide in plasma, urine, feces, liver and kidney: Application to a pharmacokinetic study of irinotecan in rats. J Chromatogr B Analyt Technol Biomed Life Sci 1015-1016:34-41
Tan, Zhi; Chen, Lu; Zhang, Shuxing (2016) Comprehensive Modeling and Discovery of Mebendazole as a Novel TRAF2- and NCK-interacting Kinase Inhibitor. Sci Rep 6:33534
Yun, Changhong; Yin, Taijun; Shatzer, Katherine et al. (2016) Determination of 7?-OH cholesterol by LC-MS/MS: Application in assessing the activity of CYP7A1 in cholestatic minipigs. J Chromatogr B Analyt Technol Biomed Life Sci 1025:76-82
Ge, Shufan; Tu, Yifan; Hu, Ming (2016) Challenges and Opportunities with Predicting in Vivo Phase II Metabolism via Glucuronidation from in Vitro Data. Curr Pharmacol Rep 2:326-338
Zeng, Min; Sun, Rongjin; Basu, Sumit et al. (2016) Disposition of flavonoids via recycling: Direct biliary excretion of enterically or extrahepatically derived flavonoid glucuronides. Mol Nutr Food Res 60:1006-19

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