title: Altered oral bioavailability and pharmacokinetics of P-glycoprotein substrates by coadministration of biochanin A.
abstract: Effects of coadministration of dietary supplement biochanin A (BA) on the pharmacokinetics of three P-glycoprotein substrates, paclitaxel, digoxin, and fexofenadine, were investigated in rats. With BA coadministration, the oral bioavailability and peak plasma concentration were markedly increased by 3.77- and 2.04-fold for paclitaxel, 1.75- and 1.71-fold for digoxin, but were reduced by 0.694- and 0.429-fold for fexofenadine, respectively. Paclitaxel is a Pgp and CYP3A substrate, the drastic increase in systemic exposure may be attributed to the synergistic inhibition of Pgp and CYP3A by BA in the intestine. Digoxin is a substrate for Pgp, CYP3A, and Oatp2. BA may suboptimally inhibit Pgp and CYP3A, resulting in a moderate increase in oral bioavailability of digoxin. Fexofenadine is a substrate for Pgp, Oatp1, Oatp2, and Oatp3. BA appears to preferentially inhibit Oatp3 over Pgp in the intestine, leading to the decreased oral absorption of fexofenadine. No significant changes in mean residence time and terminal half-life were observed for all drugs, suggesting a negligible effect of BA on their hepatic/renal elimination. These findings demonstrate the importance of interplay among uptake/efflux transporters and metabolizing enzymes. The enhanced oral absorption by BA coadministration may be exploited to improve oral bioavailability of Pgp and CYP3A substrate compounds.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, 1000 Route 202, Raritan, New Jersey 08869, USA. speng@prdus.jnj.com
authors.forename: Sean X
authors.initials: SX
authors.lastname: Peng
authors.forename: David M
authors.initials: DM
authors.lastname: Ritchie
authors.forename: Martin
authors.initials: M
authors.lastname: Cousineau
authors.forename: Earl
authors.initials: E
authors.lastname: Danser
authors.forename: Robert
authors.initials: R
authors.lastname: Dewire
authors.forename: Jane
authors.initials: J
authors.lastname: Floden
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019833:Genistein / Q000737:chemistry*; D006207:Half-Life; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002316:Cardiotonic Agents; D006634:Histamine H1 Antagonists; D004077:Digoxin; D016593:Terfenadine; D019833:Genistein; C093230:fexofenadine; D017239:Paclitaxel; C004541:biochanin A