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Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

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Abstract

This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure–activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes. The percent inhibition and IC50 of each flavonoid were calculated and used to develop SAR and QSAR. The most effective flavonoid was orally co-administered in vivo with a cholesterol-reducing drug, fluvastatin, which is normally metabolized by CYP2C. The most potent CYP2C inhibitor identified in vitro was tamarixetin (IC50 = 1.4 μM). This flavonoid enhanced the oral bioavailability of fluvastatin in vivo, producing a >2-fold increase in the area under the concentration–time curve and in the peak plasma concentration. SAR analysis indicated that the presence of a 2,3-double bond in the C ring, hydroxylation at positions 5, 6, and 7, and glycosylation had important effects on flavonoid–CYP2C interactions. These findings should prove useful for predicting the inhibition of CYP2C activity by other untested flavonoid-like compounds. In the present study, tamarixetin significantly inhibited CYP2C activity in vitro and in vivo. Thus, the use of tamarixetin could improve the therapeutic efficacy of drugs with low bioavailability.

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ACKNOWLEDGMENTS

This work was supported in part by Taiwan Biotech Co., Ltd. and Novartis Co., Ltd. in Taiwan. We are grateful to Dr. Ueng Yune-Fang for her technical assistance.

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Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China

    Hong-Jaan Wang, Tung-Yuan Shih & Oliver Yoa-Pu Hu

  2. School of Pharmacy, National Defense Medical Center, 161 Minchuan East Road, Sec. 6, Taipei, Taiwan, 114, Republic of China

    Li-Heng Pao, Cheng-Huei Hsiong & Oliver Yoa-Pu Hu

  3. Department of Nutrition and Health Science, Chang Gung University of Science and Technology, Taoyuan County, Taiwan, Republic of China

    Li-Heng Pao

  4. School of Public Health, National Defense Medical Center, Taipei, Taiwan, Republic of China

    Meei-Shyuan Lee

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  1. Hong-Jaan Wang
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Correspondence to Oliver Yoa-Pu Hu.

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Wang, HJ., Pao, LH., Hsiong, CH. et al. Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship. AAPS J 16, 258–268 (2014). https://doi.org/10.1208/s12248-013-9549-4

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  • DOI: https://doi.org/10.1208/s12248-013-9549-4

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