Influence of cytarabine and cyclophosphamide on the disposition kinetics of cyclosporin A after bone marrow transplantation.

ABSTRACT

The blood concentration of cyclosporin A (CyA) often gradually increases or is unstable in the early period of immunotherapy in bone marrow transplantation patients. In the protocol for bone marrow transplantation, pretreatment with cytarabine (Ara-C) and cyclophosphamide (CPA) is employed. We examined the influence of Ara-C and CPA on the disposition kinetics of CyA, in using rats to define the mechanism for the observation. Rats were intravenously administered daily with Ara-C (120 mg/kg/day) or CPA (60 mg/kg/day) intravenously for 2 days and were then intravenously given CyA (10 mg/kg). The blood concentration of CyA after intravenous administration of CyA at 1 day after the last administration of CPA was significantly lower and the total clearance was significantly larger than those in the vehicle control rats, while the blood concentration and the pharmacokinetic parameters of CyA were unchanged after Ara-C treatment. The expression of mdr1a, mdr1b, and CY3A2 mRNAs, and the levels of the corresponding proteins in the liver were increased after the CPA treatment. These CPA-induced changes were almost fully reversed to the control levels by 2 weeks. Thus, our results indicate that the decrease of blood CyA concentration induced is a consequence of the induction of P-glycoprotein and CYP3A in the liver by the CPA treatment, and these changes are reversed within 2 weeks after the transplantation.