Interactions between the flavonoid biochanin A and P-glycoprotein substrates in rats: in vitro and in vivo.
The purpose of this study was to investigate the in vitro and in vivo interactions between flavonoids and P-glycoprotein (P-gp) substrates. The inhibitory effects of flavonoids on P-gp were determined by accumulation studies in P-gp-overexpressing MCF-7/ADR cells using daunomycin (DNM) as a model substrate. Morin, phloretin, biochanin A, chalcone, and silymarin significantly increased DNM accumulation by greater than 2.5-fold, suggesting they are P-gp inhibitors. To explore potential in vivo interactions of flavonoids with P-gp, the effect of biochanin A on the pharmacokinetics of the P-gp substrates doxorubicin, cyclosporine A, and paclitaxel was investigated. In contrast to the in vitro results, intraperitoneal or oral administration of biochanin A did not significantly change the pharmacokinetics of doxorubicin and cyclosporine A. Moderate interaction was observed between biochanin A and paclitaxel, resulting in lower AUC values after both i.v. and oral administration of paclitaxel. The disconnect between the in vitro and in vivo data suggests that P-gp interactions mediated by biochanin A may be limited due to its poor bioavailability and rapid clearance. It is also possible that other transporters or metabolizing enzymes are more important in the in vivo disposition of doxorubicin, cyclosporine A, and paclitaxel than P-gp.
Zhang
Shuzhong
S
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, USA.
Sagawa
Kazuko
K
Arnold
Robert D
RD
Tseng
Elaine
E
Wang
Xiaodong
X
Morris
Marilyn E
ME
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019833:Genistein; C004541:biochanin A; D003630:Daunorubicin