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) cycle. 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.) injection. 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 rhythmicity corresponded to the dosing time-dependent difference of PGE2 levels in thalamus after IFN-alpha injection, but it did not correspond to that of plasma IFN-alpha concentrations. A significant dosing time-dependent difference was also demonstrated for 2'-5'oligoadenylate synthetase activities, as an index of antiviral activity, in plasma and liver at 24 hr after IFN-alpha injection. It was related to the rhythmicity in plasma IFN-alpha concentrations that was caused by the rhythmicity in clearance of IFN-alpha. The choice of the most appropriate time of day for drug administration may help to achieve rational chronotherapeutics of IFN-alpha in certain experimental and clinical situations.