Vol. 294, Issue 2, 488-493, August 2000

Basis for Dosing Time-Dependent Changes in the Antiviral Activity of Interferon- in Mice¹

Shigehiro Ohdo, De-Sheng Wang, Satoru Koyanagi, Hiroshi Takane, Kouichi Inoue, Hironori Aramaki, Eiji Yukawa and Shun Higuchi

Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Graduate School, Kyushu University (S.O., D.-S.W., S.K., H.T., K.I., E.Y., S.H.); and Department of Molecular Biology, Daiichi College of Pharmaceutical Sciences (H.A.), Fukuoka, Japan

The influence of dosing time on the pharmacological effect (antiviral activity) of interferon- (IFN-), and the pharmacological and pharmacokinetic mechanisms, were investigated in ICR male mice under a 12-h light/dark cycle (lights on from 7:00 AM to 7:00 PM). 2'-5'Oligoadenylate synthetase activity in plasma at 24 h after IFN- (10 MI.U./kg, i.v.) injection, as an index of antiviral activity, was significantly higher for injections given at 9:00 AM than for injections given at 9:00 PM (P < .05). The uptake of [³H]thymidine by lymphocytes after 24-h incubation with IFN-, as an index of lymphocyte-stimulating effect, was significantly higher in cells obtained at 9:00 AM than in the cells obtained at 9:00 PM (P < .01). The number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN- were significantly higher in the cells obtained at 9:00 AM than at 9:00 PM (P < .05). A significant dosing time-dependent difference was demonstrated for the pharmacokinetic parameters of IFN-, which showed higher clearance for injections given at 9:00 PM than for those at 9:00 AM (P < .05). The metabolism of IFN- was significantly higher in kidney obtained at 9:00 PM than at 9:00 AM (P < .05). These findings support that choosing the most appropriate time of day for administration of IFN-, associated with the rhythmicity of IFN- receptor function and IFN- pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.