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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Shigehiro Ohdo, De-Sheng Wang, Satoru Koyanagi, Hiroshi Takane, Kouichi Inoue, Hironori Aramaki, Eiji Yukawa and Shun Higuchi
Journal of Pharmacology and Experimental Therapeutics August 2000, 294 (2) 488-493;
Shigehiro Ohdo
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De-Sheng Wang
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Satoru Koyanagi
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Hiroshi Takane
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Kouichi Inoue
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Hironori Aramaki
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Eiji Yukawa
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Shun Higuchi
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Abstract

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.

Footnotes

  • Send reprint requests to: Shigehiro Ohdo, Ph.D., Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Graduate School, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582 Japan. E-mail:ohdo{at}shunsan.phar.kyushu-u.ac.jp.

  • ↵1 This research was supported by Grant-in-Aid 00223884 for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture, Japan (S.O.), a grant-in-aid from the Tokyo Biochemical Research Foundation, a grant-in-aid from the Nakatomi Foundation, and a grant-in-aid from Nippon Boehringer Ingelheim.

  • Abbreviations:
    IFN-α
    interferon-α
    MI.U.
    mega international units
    ISGF
    interferon-stimulated gene factor
    2′-5′OAS
    2′-5′oligoadenylate synthetase
    CL
    clearance
    FBS
    fetal bovine serum
    TCA
    trichloroacetic acid
    ELISA
    enzyme-linked immunosorbent assay
    • Received January 4, 2000.
    • Accepted April 28, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 2
1 Aug 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Shigehiro Ohdo, De-Sheng Wang, Satoru Koyanagi, Hiroshi Takane, Kouichi Inoue, Hironori Aramaki, Eiji Yukawa and Shun Higuchi
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 488-493;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

Shigehiro Ohdo, De-Sheng Wang, Satoru Koyanagi, Hiroshi Takane, Kouichi Inoue, Hironori Aramaki, Eiji Yukawa and Shun Higuchi
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 488-493;
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