Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship

Hong Jaan Wang, Li Heng Pao, Cheng Huei Hsiong, Tung Yuan Shih, Meei Shyuan Lee, Oliver Yoa Pu Hu

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)258-268
Number of pages11
JournalAAPS Journal
Volume16
Issue number2
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Fingerprint

Quantitative Structure-Activity Relationship
Flavonoids
Biological Availability
fluvastatin
Pharmaceutical Preparations
Structure-Activity Relationship
Inhibitory Concentration 50
Tolbutamide
cytochrome P-450 CYP2C subfamily
Liver Microsomes
Hydroxylation
Glycosylation
Isoenzymes
Cholesterol
Enzymes

Keywords

  • bioavailability
  • CYP2C
  • flavonoid
  • structure-activity relationship
  • tamarixetin

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship. / Wang, Hong Jaan; Pao, Li Heng; Hsiong, Cheng Huei; Shih, Tung Yuan; Lee, Meei Shyuan; Hu, Oliver Yoa Pu.

In: AAPS Journal, Vol. 16, No. 2, 01.01.2014, p. 258-268.

Research output: Contribution to journalArticle

Wang, Hong Jaan ; Pao, Li Heng ; Hsiong, Cheng Huei ; Shih, Tung Yuan ; Lee, Meei Shyuan ; Hu, Oliver Yoa Pu. / Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship. In: AAPS Journal. 2014 ; Vol. 16, No. 2. pp. 258-268.
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