Chronopharmacology for deoxyspergualin - Toxicity and efficacy in the rat

Background Deoxyspergualin (DSG), a potent immunosuppressive drug, has been clinically used as a rescue therapy for acute graft rejection. However, DS G has severe adverse effects that limits its use. Here, we examined the opt imized therapeutic protocol for DSG using chronopharmacological profiles of it. Methods. First, a dosing time-dependent difference in the toxicity and effi cacy of DSG was determined using a heterotopic heart transplantation model. Second, chronokinetics of DSG were examined to reveal the mechanism for do sing time-dependent differences in the effect. Results. In rats treated with DSG at the active period, bone marrow suppres sion and damage of small intestine were significantly severe. However, no s ignificant difference was found in cardiac allograft survival and pharmacok inetics according to the timing of drug administration. Conclusions. The toxicity of DSG varied with the dosing time, whereas its e fficacy did not. The chronopharmacological approach may provide merits for immunosuppressive therapy with DSG in clinical organ transplantation.