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

  1. Shigehiro Ohdo1,
  2. De-Sheng Wang1,
  3. Satoru Koyanagi1,
  4. Hiroshi Takane1,
  5. Kouichi Inoue1,
  6. Hironori Aramaki2,
  7. Eiji Yukawa1 and
  8. Shun Higuchi1
  1. 1Department 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 2Department of Molecular Biology, Daiichi College of Pharmaceutical Sciences (H.A.), Fukuoka, Japan

    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.
    « Previous | Next Article »Table of Contents

    This Article

    1. JPET August 1, 2000 vol. 294 no. 2 488-493
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 331 (2)
    1. Current Issue
    1. Alert me to new issues of JPET