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
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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.
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↵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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