title: Effects of baicalein on the pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats: possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by baicalein.
abstract: The purpose of this study was to investigate the effects of baicalein on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats. Tamoxifen and baicalein interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in baicalein being taken concomitantly with tamoxifen as a combination therapy to treat orprevent cancer diseases. Pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined in rats after an oral administration of tamoxifen (10 mg/kg) to rats in the presence and absence of baicalein (0.5, 3, and 10 mg/kg). Compared to the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve and the peak plasma concentration of tamoxifen were significantly increased by 47.6-89.1% and 54.8-100.0%, respectively. The total body clearance was significantly decreased (3 and 10 mg/kg) by baicalein. Consequently, the absolute bioavailability of tamoxifen in the presence of baicalein (3 and 10 mg/kg) was significantly increased by 47.5-89.1% compared with the oral control group (20.2%). The metabolite-parent AUC ratio of tamoxifen was significantly reduced, implying that the formation of 4-hydroxytamoxifen was considerably affected by baicalein. Baicalein enhanced the oral bioavailability of tamoxifen, which may be mainly attributable to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the small intestine and/or in the liver, and inhibition of the P-gp efflux pump in the small intestine and/or reduction of total body clearance by baicalein.
authors.affiliation: BK21 project team, College of Pharmacy, Chosun University, Gwangju 501759, Korea.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Minhee
authors.initials: M
authors.lastname: Kim
authors.forename: HongSeok
authors.initials: H
authors.lastname: Choi
authors.forename: JunShik
authors.initials: J
authors.lastname: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D044950:Flavanones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D049990:Membrane Transport Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018931:Antineoplastic Agents, Hormonal; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D044950:Flavanones; D049990:Membrane Transport Modulators; D011994:Recombinant Proteins; D013629:Tamoxifen; C016601:afimoxifene; C006680:baicalein; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A