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
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
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
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
Ma, Yong; Gao, Song; Hu, Ming (2015) Quantitation of celecoxib and four of its metabolites in rat blood by UPLC-MS/MS clarifies their blood distribution patterns and provides more accurate pharmacokinetics profiles. J Chromatogr B Analyt Technol Biomed Life Sci 1001:202-11
Sun, Rongjin; Zeng, Min; Du, Ting et al. (2015) Simultaneous determinations of 17 marker compounds in Xiao-Chai-Hu-Tang by LC-MS/MS: Application to its pharmacokinetic studies in mice. J Chromatogr B Analyt Technol Biomed Life Sci 1003:12-21
Yan, Tongmeng; Lu, Linlin; Xie, Cong et al. (2015) Severely Impaired and Dysregulated Cytochrome P450 Expression and Activities in Hepatocellular Carcinoma: Implications for Personalized Treatment in Patients. Mol Cancer Ther 14:2874-86
Yang, Guangyi; Gao, Song; Sun, Rongjin et al. (2015) Development and validation of an UPLC-MS/MS method for the quantification of columbin in biological matrices: Applications to absorption, metabolism, and pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci 1002:13-8
Yan, Tongmeng; Gao, Song; Peng, Xiaojuan et al. (2015) Significantly decreased and more variable expression of major CYPs and UGTs in liver microsomes prepared from HBV-positive human hepatocellular carcinoma and matched pericarcinomatous tissues determined using an isotope label-free UPLC-MS/MS method. Pharm Res 32:1141-57
Dai, Peimin; Zhu, Lijun; Luo, Feifei et al. (2015) Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids. AAPS J 17:723-36
Jiamboonsri, Pimsumon; Pithayanukul, Pimolpan; Bavovada, Rapepol et al. (2015) A validated liquid chromatography-tandem mass spectrometry method for the determination of methyl gallate and pentagalloyl glucopyranose: application to pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci 986-987:12-7

Showing the most recent 10 out of 65 publications