Basis for dosing time-dependent changes in the antiviral activity of interferon-α in mice

The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-α (IFN-α), 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-α (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- α, 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-α 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-α, which showed higher clearance for injections given at 9:00 PM than for those at 9:00 AM (P < .05). The metabolism of IFN-α 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-α, associated with the rhythmicity of IFN-α receptor function and IFN-α pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.