title: Basis for dosing time-dependent changes in the antiviral activity of interferon-alpha in mice.
abstract: The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-alpha (IFN-alpha), 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-alpha (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 [(3)H]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). The number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN-alpha 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-alpha, which showed higher clearance for injections 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 at 9:00 AM (P <.05). These findings support that choosing the most appropriate time of day for administration of IFN-alpha, associated with the rhythmicity of IFN-alpha receptor function and IFN-alpha pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.
authors.affiliation: Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Graduate School, Kyushu University, Fukuoka, Japan. ohdo@shunsan.phar.kyushu-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Ohdo
authors.forename: D S
authors.initials: DS
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Koyanagi
authors.forename: H
authors.initials: H
authors.lastname: Takane
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Aramaki
authors.forename: E
authors.initials: E
authors.lastname: Yukawa
authors.forename: S
authors.initials: S
authors.lastname: Higuchi
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002909:Chronobiology Phenomena; D002940:Circadian Rhythm / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000097:blood; D004334:Drug Administration Schedule; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007457:Iodine Radioisotopes; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010750:Phosphoproteins / Q000096:biosynthesis / Q000097:blood; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism / Q000502:physiology; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D007457:Iodine Radioisotopes; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D015088:2',5'-Oligoadenylate Synthetase