Dosing time-dependent pharmacological effects of anti-metabolites for rat cardiac graft.

ABSTRACT

Antimetabolites such as methotrexete and 6-mercaptopurine have been shown to have circadian variations in their toxicities. However, chronopharmacological profiles of mizoribine (Miz) that is newly synthesized as an anti-metabolic agent for immunosuppression, have not been evaluated. In this study, we examined the dosing time-dependent alterations in the pharmacokinetics and pharmacodynamics of Miz. In addition, chronopharmacology of azathiopurine (Aza) was also evaluated to compare with that of Miz. Initially, Miz (10 and 20 mg/kg) or Aza (20 mg/kg) was orally administered at 800 hr or 2000 hr for 3 weeks to rats. To reveal the dosing time-dependent difference of pharmacokinetics, Miz (20 mg/kg) was orally given at 800 hr or 2000 hr and blood was obtained for 12 hours. Finally, Miz (20 mg/kg) or Aza (20 mg/kg) was administered at 800 hr or 2000 hr to rats with heterotopic allogeneic heart grafts. The Miz group treated at 800 hr and Aza group treated at 2000 hr showed severe myelosuppression compared with their each opposite dosing time. AUC of Miz in the morning trial was twice as high as that in the evening trial. The graft survival durations of the Miz- and Aza-treated groups were significantly longer than those of the respective control groups, but were not affected by dosing time of each agent. These results suggest that the toxicity, but not efficacy of Miz is varied with the dosing time. The chronotoxicological phenomenon of Miz might be, at least in part, explained by the dosing time-dependent difference in serum drug concentrations and apparent clearance.