Effect of genistein on the pharmacokinetics of paclitaxel administered orally or intravenously in rats.
As many anticancer agents paclitaxel is a substrate for ATP-binding cassette (ABC) transporters such as P-glycoprotein-mediated efflux, and its metabolism in humans mainly catalyzed by CYP 3A4 and 2C8. Genistein, an isoflavonoid, is supposed to be an inhibitor of some ABC transporters, and its oxidative metobolism catalyzed by CYP 3A4 and 2C8. The purpose of this study was to investigate the effect of orally administered genistein on the pharmacokinetics of paclitaxel administered through oral and intravenous (i.v.) route in rats. A single dose of paclitaxel administered orally (30 mg/kg) or i.v. (3mg/kg) alone or 30 min after oral administration of genistein (3.3mg/kg or 10mg/kg). The presence of 10mg/kg genistein significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC, 54.7% greater) of orally administered paclitaxel, which was due to the significantly (p<0.05) decreased total plasma clearance (CL/F) of paclitaxel (35.2% lower). Genistein also increased the peak concentration (C(max)) of paclitaxel significantly (p<0.05 by 3.3mg/kg, 66.8% higher; p<0.01 by 10mg/kg, 91.8% higher). Consequently, the absolute bioavailability (F) of paclitaxel in the presence of genistein was 0.020-0.025, which was elevated more than the control group (0.016); and the relative bioavailability (Fr) of orally administered paclitaxel was increased from 1.26- to 1.55-fold. Ten milligrams per kilogram genistein also significantly (p<0.05) increased the AUC (40.5% greater) and reduced the total clearance (CLt, 30% lower) of i.v. administered paclitaxel. The presence of genistein improved the systemic exposure of paclitaxel in this study. The pharmacokinetic interaction between them should be taken into consideration when paclitaxel is used with genistein or the dietary supplements full of genistein.
Li
Xiuguo
X
College of Pharmacy, Chosun University, Gwangju 501-759, Republic of Korea.
Choi
Jun-Shik
JS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019833:Genistein / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D004366:Nonprescription Drugs; D017239:Paclitaxel / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D048789:Phytoestrogens / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004366:Nonprescription Drugs; D048789:Phytoestrogens; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel