ABSTRACT
OBJECTIVES: It has been reported that docetaxel is a P-glycoprotein substrate and is metabolized via the cytochrome P450 (CYP) 3A subfamily in rats. Tesmilifene is a substrate of the CYP3A subfamily and is an inhibitor of P-glycoprotein. Thus, the effects of various doses of tesmilifene on the pharmacokinetics of intravenous and orally administered docetaxel have been investigated in rats. METHODS: Docetaxel (20 mg/kg as base) was administered intravenously and orally without and with tesmilifene (5, 10, and 20 mg/kg) in rats. KEY FINDINGS: After intravenous administration of docetaxel with tesmilifene, the values of nonrenal clearance (CL(NR)) and area under the plasma concentration-time (AUC) for docetaxel were comparable with those without tesmilifene. Tesmilifene did not increase the values of AUC or of absolute oral bioavailability (F) for docetaxel after oral administration of docetaxel with tesmilifene. CONCLUSIONS: The inhibition for the metabolism of docetaxel via hepatic and intestinal CYP3A subfamily, and inhibition of P-glycoprotein-mediated efflux of docetaxel in the intestine by tesmilifene were almost negligible. The extremely low value of F for docetaxel was due to the incomplete absorption from the gastrointestinal tract and considerable first-pass metabolism of docetaxel in rats.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cytochrome P-450 CYP3A/metabolism , Phenyl Ethers/administration & dosage , Taxoids/administration & dosage , Taxoids/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Oral , Animals , Antineoplastic Agents/blood , Area Under Curve , Biotransformation , Docetaxel , Drug Interactions , Injections, Intravenous , Male , Metabolic Clearance Rate , Phenyl Ethers/metabolism , Rats , Rats, Sprague-Dawley , Taxoids/bloodABSTRACT
The pharmacokinetics of SP-8203, a potential protective agent for the treatment of cerebral infarction, were evaluated after its intravenous (10, 20 and 30 mg/kg) and oral (10, 20, 30 and 100 mg/kg) administration in rats. After the intravenous administration of SP-8203, the AUCs of SP-8203 were dose-dependent; the dose-normalized AUCs were significantly greater with increasing doses. After the oral administration of SP-8203, plasma concentrations of SP-8203 were much lower than those after intravenous administration. This could be due to considerable hepatic and intestinal metabolism and the high percent of the dose recovered from the gastrointestinal tract (including its contents and feces) at 24 h as unchanged drug.
