The purpose of this study was to investigate the effect of imatinib mesilate on the disposition kinetics of ciclosporin in rats. The blood concentration-time course and pharmacokinetic parameters of ciclosporin did not significantly change after intravenous injection of ciclosporin (10 mg kg(-1)) in rats treated with imatinib mesilate (50 mg kg(-1)) as compared with a control. When ciclosporin (10 mg kg(-1)) was orally administered, the time course, area under the curve, bioavailability and peak blood concentration of ciclosporin were significantly increased in rats that had been treated with imatinib mesilate 2 h before ciclosporin administration as compared with the control. Because both drugs are transported via P-glycoprotein and breast cancer resistance protein and metabolized by cytochrome P450 3A2, the interaction of imatinib mesilate with these proteins may be responsible for the increased intestinal absorption of ciclosporin in rats. These results indicate that imatinib mesilate enhanced the intestinal absorption of ciclosporin in rats with only the oral administration of ciclosporin, suggesting that our results support clinical data. In addition, imatinib mesilate may increase the pharmacological effects and possibly toxicity of ciclosporin.

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Cyclosporin A (CyA) and azole antifungals are clinically co-administered to patients after allogeneic hematopoietic stem cell transplantation (HSCT). Since CyA is a substrate of P450 (CYP3A4) and/or P-glycoprotein in the liver and the intestine, concomitant use of CyA and azole antifungals might increase the concentration of CyA in the blood. The purpose of this study was to evaluate the effects of antifungals on the blood concentration of CyA in allogeneic HSCT recipients. When CyA was orally administered, the magnitude of drug interactions between CyA and the antifungals on CyA concentration were: oral itraconazole (ITZ) solution > voriconazole (VCZ) tablet > ITZ capsule > fluconazole (FCZ) capsule. The concentration/dose ratio of CyA increased with each antifungal but the difference from control was only significant with oral ITZ solution (P<0.001). When CyA was intravenously (iv.) administered, the magnitude of drug interactions on CyA clearance was: iv. ITZ injection and VCZ tablet > oral ITZ solution > FCZ capsule > iv. fosfluconazole injection and ITZ capsule. Significant decreases in CyA clearance versus control were seen with iv. ITZ injection (P<0.001), VCZ tablet and oral ITZ solution (P<0.05). The present study confirmed that the magnitude of the drug interactions between CyA and azole antifungals varies by dosage form as well as by the potency of the azole inhibitor. These results provide a better understanding of the drug interactions between immunosuppressants and azole antifungals. In addition, this information may contribute to the effectiveness and safety of immunosuppressant therapy.