Chronopharmacology for deoxyspergualin: toxicity and efficacy in the rat
Uchida, H.; Kobayashi, E.; Matsuda, K.; Mizuta, K.; Sugimoto, K.; Kawarasaki, H.; Hashizume, K.; Fujimura, A.
Transplantation 67(9): 1269-1274
1999
ISSN/ISBN: 0041-1337 PMID: 10342320 Document Number: 511432
Background. Deoxyspergualin (DSG), a potent immunosuppressive drug, has been clinically used as a rescue therapy for acute graft rejection. However, DSG has severe adverse effects that limits its use. Here, we examined the optimized therapeutic protocol for DSG using chronopharmacological profiles of it. Methods. First, a dosing time-dependent difference in the toxicity and efficacy of DSG was determined using a heterotopic heart transplantation model. Second, chronokinetics of DSG were examined to reveal the mechanism for dosing time-dependent differences in the effect. Results. In rats treated with DSG at the active period, bone marrow suppression and damage of small intestine were significantly severe. However, no significant difference was found in cardiac allograft survival and pharmacokinetics according to the timing of drug administration. Conclusions. The toxicity of DSG varied with the dosing time, whereas its efficacy did not. The chronopharmacological approach may provide merits for immunosuppressive therapy with DSG in clinical organ transplantation.