title: Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship.
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.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: Hong-Jaan
authors.initials: HJ
authors.lastname: Wang
authors.forename: Li-Heng
authors.initials: LH
authors.lastname: Pao
authors.forename: Cheng-Huei
authors.initials: CH
authors.lastname: Hsiong
authors.forename: Tung-Yuan
authors.initials: TY
authors.lastname: Shih
authors.forename: Meei-Shyuan
authors.initials: MS
authors.lastname: Lee
authors.forename: Oliver Yoa-Pu
authors.initials: OY
authors.lastname: Hu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004032:Diet; D004187:Disaccharides / Q000737:chemistry / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000493:pharmacokinetics; D005419:Flavonoids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000077340:Fluvastatin; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D021281:Quantitative Structure-Activity Relationship; D011794:Quercetin / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C516573:4'-hydroxytolbutamide; D065607:Cytochrome P-450 Enzyme Inhibitors; D004187:Disaccharides; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D005419:Flavonoids; D007211:Indoles; C400322:cytochrome P-450 CYP2C subfamily; D000077340:Fluvastatin; C508967:tamarixetin; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D011794:Quercetin