CHRONOPHARMACOLOGICAL STUDY OF INTERFERON-ALPHA IN MICE

The influence of dosing time on the pharmacological effects (fever and antiviral activity) and the pharmacokinetics of interferon-alpha (IFN -alpha) was investigated in ICR male mice under light-dark (12:12) cyc le. There was a significant circadian rhythm in rectal temperature, as an index of fever, at 0.5 hr after IFN-alpha (10.0 MIU/kg i.v.) injec tion. The rhythmic pattern resembled overall the rhythm that occurs in the nondrugged state. However, the percent change from basal level of rectal temperature varied according to the dosing time. The rhythmici ty corresponded to the dosing time-dependent difference of PGE(2)level s in thalamus after IFN-alpha injection, but it did not correspond to that of plasma IFN-alpha concentrations. A significant dosing time-dep endent difference was also demonstrated for 2'-5'oligoadenylate synthe tase activities, as an index of antiviral activity, in plasma and live r at 24 hr after IFN-alpha injection. It was related to the rhythmicit y in plasma IFN-alpha concentrations that was caused by the rhythmicit y in clearance of IFN-alpha. The choice of the most appropriate time o f day for drug administration may help to achieve rational chronothera peutics of IFN-alpha in certain experimental and clinical situations.