A quantitative structure-activity relationship for the modulation effects of flavonoids on p-glycoprotein-mediated transport.
P-Glycoprotein accounts for multidrug resistance in chemotherapy patients and contributes to reduced oral bioavailability and distribution of drugs in the brain. The aim of this study was to establish the qualitative and quantitative structure-activity relationships (QSAR) of flavonoid modulation effects on P-glycoprotein (P-gp)'s function. Using human colorectal adenocarcinoma (HCT15) cells as an in vitro model and fexofenadine as a P-gp substrate, the modulation effects on P-gp at three concentration levels of 22 representative compounds from four flavonoid families were evaluated. Results showed that the modulation (enhanced or inhibitory) effects could be divided into three ranges designated as enhanced (<100%) as compared to the control, low inhibitory (100-217%) and high inhibitory (>217%) as compared to verapamil. An optimal QSAR was constructed for Y1 (adjusted R(2)=0.4798), Y2 (adjusted R(2)=0.6809), and Y3 (adjusted R(2)=0.5902), respectively. This was further confirmed by a highly correlated plot of the predicted percent inhibition against observed values from a respective QSAR equation.
Sheu
Ming-Thau
MT
College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
Liou
Yi-Bo
YB
Kao
Yu-Han
YH
Lin
Ying-Ku
YK
Ho
Hsiu-O
HO
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D016593:Terfenadine / Q000031:analogs & derivatives / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005419:Flavonoids; D016593:Terfenadine; C093230:fexofenadine