Abstract
The influence of dosing time on the pharmacological effects (fever and antiviral activity) and the pharmacokinetics of interferon-α (IFN-α) was investigated in ICR male mice under light-dark (12:12) cycle. There was a significant circadian rhythm in rectal temperature, as an index of fever, at 0.5 hr after IFN-α (10.0 MIU/kg i.v.) injection. The rhythmic pattern resembled overall the rhythm that occurs in the nondrugged state. However, the percent change from basal level of rectal temperature varied according to the dosing time. The rhythmicity corresponded to the dosing time-dependent difference of PGE2 levels in thalamus after IFN-α injection, but it did not correspond to that of plasma IFN-α concentrations. A significant dosing time-dependent difference was also demonstrated for 2′-5′oligoadenylate synthetase activities, as an index of antiviral activity, in plasma and liver at 24 hr after IFN-α injection. It was related to the rhythmicity in plasma IFN-α concentrations that was caused by the rhythmicity in clearance of IFN-α. The choice of the most appropriate time of day for drug administration may help to achieve rational chronotherapeutics of IFN-α in certain experimental and clinical situations.
Footnotes
-
Send reprint requests to: Shigehiro Ohdo, Ph.D., Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812 Japan.
- Abbreviations:
- IFN-α
- interferon-α
- 2′-5′OAS
- 2′-5′oligoadenylate synthetase
- CL
- clearance
- Vc
- central volume of distribution
- K12
- distribution rate constant from central to peripheral compartment
- K21
- distribution rate constant from peripheral to central compartment
- Received December 27, 1996.
- Accepted June 12, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|