Effects of aprepitant on the pharmacokinetics of imatinib and its main metabolite in rats.

Aprepitant (APT), an antiemetic drug belonging to the class of substance P antagonists is efficiently used in both acute and delayed chemotherapy-induced nausea and vomiting. Nausea and vomiting induced by imatinib (IMA) as a chemotherapeutic drug could be reduced by APT. This study investigated the effect of APT on the pharmacokinetics of IMA and its major metabolite N-desmethyl imatinib (N-D IMA) in rats and the mechanism of this drug-drug interaction. The results indicated that after 3 days of pretreatment with APT (10 mg/kg), the blood concentration of IMA was decreased in both of oral and intravenous routes of IMA administration compared to vehicle treated rats, whereas the blood concentration of N-D IMA was not significantly changed. The total clearance (CL/F) of oral and intravenous given IMA was increased by 1.41 and 1.32-fold, and the bioavailability was greatly decreased about 30.43% and 24.40% respectively. At this time, the P-gp and the hepatic CYP3A1 were increased at both the mRNA and protein levels. These results demonstrated that ingestion of APT will decrease the bioavailability of IMA to a significant extent in rats and the drug-drug interaction between APT and IMA appears to be due to modulation of P-gp and CYP3A1.