Abstract
Background: This study was designed to investigate the effects of dasatinib and nilotinib on the pharmacokinetics of cyclosporine in rats, as these drugs have been reported to be cytochrome P450 3A4 (CYP3A4) substrates.
Methods: Control and test groups (n = 5) were treated with vehicle and dasatinib (4 mg/kg, and 16 mg/kg, oral) or nilotinib (94 mg/kg, oral), respectively, for 8 consecutive days. On day 8, all groups were administered cyclosporine (30 mg/kg) 1 h after the last dose of dasatinib or nilotinib. Blood was collected from the retro-orbital plexus in heparinized tubes at different time points (0, 0.5, 1, 1.5, 2, 3.5, 8, 12, and 24 h). The cyclosporine concentration in blood samples was determined by ultra-performance liquid chromatography-tandem mass spectrometry. The effects of dasatinib on CYP3A2 mRNA and protein expression levels were also investigated.
Results: Dasatinib significantly reduced the maximum blood concentration (Cmax) of cyclosporine by 85.7%, and increased hepatic and intestinal CYP3A2 mRNA and protein expression levels by 2.4- and 1.25-fold, respectively, compared to those in the controls (p < 0.05). On the other hand, nilotinib had no significant effects on cyclosporine pharmacokinetic parameters.
Conclusions: Dasatinib significantly reduced cyclosporine exposure, which was most probably related to the induction of CYP3A-mediated cyclosporine metabolism. (C) 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.