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, 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.
Uchida
H
H
Department of Clinical Pharmacology, Jichi Medical School, Tochigi, Japan.
Kobayashi
E
E
Matsuda
K
K
Mizuta
K
K
Sugimoto
K
K
Kawarasaki
H
H
Hashizume
K
K
Fujimura
A
A
D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology; D004334:Drug Administration Schedule; D006146:Guanidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D016042:Transplantation, Heterotopic
D006146:Guanidines; D007166:Immunosuppressive Agents; C037258:gusperimus