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

The influence of dosing time on the pharmacological effect (antiviral activ ity) of interferon-alpha (IFN-alpha), and the pharmacological and pharmacok inetic mechanisms, were investigated in ICR male mice under a 12-h light/da rk cycle (lights on from 7: 00 AM to 7: 00 PM). 2'-5' Oligoadenylate synthe tase activity in plasma at 24 h after IFN-alpha (10 MI. U./kg, i.v.) inject ion, as an index of antiviral activity, was significantly higher for inject ions given at 9:00 AM than for injections given at 9:00 PM (P<.05). The upt ake of [H-3] thymidine by lymphocytes after 24-h incubation with IFN-alpha, 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). T he number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN-alpha were signi ficantly 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 phar macokinetic parameters of IFN-alpha, which showed higher clearance for inje ctions given at 9: 00 PM than for those at 9:00 AM (P<.05). The metabolism of IFN-alpha was significantly higher in kidney obtained at 9: 00 PM than a t 9: 00 AM (P<.05). These findings support that choosing the most appropria te time of day for administration of IFN-alpha, associated with the rhythmi city of IFN-alpha receptor function and IFN-alpha pharmacokinetics, may inc rease the antiviral activity in experimental and clinical situations.