QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.055657v1 308/1/378    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Akagi, T. Articles by Ohdo, S. Search for Related Content PubMed PubMed Citation Articles by Akagi, T. Articles by Ohdo, S.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Chronopharmacology of Melatonin in Mice to Maximize the Antitumor Effect and Minimize the Rhythm Disturbance Effect

Departments of Clinical Pharmacokinetics (T.A., K.U., S.I., E.Y., S.H., S.O.) and Bio-Analytical Chemistry (K.H., K.Z.), Division of Pharmaceutical Science, Graduate School, Kyushu University, Fukuoka, Japan

The influence of dosing time on the antitumor effect and the rhythm disturbance effect of melatonin (MLT) was investigated in ICR male mice under a light/dark (12:12) cycle. In tumor-bearing mice, the antitumor effect of MLT (1 mg/kg intraperitoneal) was most effective in the dark phase; and the rhythm disturbance effect of MLT on the locomotor activity was more serious in the light phase than in the dark phase. The antitumor effect and the rhythm disturbance effect of MLT increased when the specific binding of MLT receptor in target tissues, tumor or suprachiasmatic nucleus, increased and they decreased when the level decreased. Furthermore, because luzindole, an MT₁ and MT₂ blocker, caused the antitumor effect or rhythm disturbance effect of MLT to decrease, it is suggested that the time-dependent change of the pharmacological effects of MLT were influenced by that of MLT receptor(s) function. On the other hand, there was no significant dosing time-dependent change of MLT concentration in tumor or brain after injection. Thus, the pharmacokinetic factor does not seem to contribute to the dosing time-dependent effect of MLT. These results suggest that by choosing the most suitable dosing time for MLT, the efficacy of the drug can be increased, and the toxicity of the drug can be decreased in certain experimental and clinical situations.

Address correspondence to: Dr. Shigehiro Ohdo, 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}phar.kyushu-u.ac.jp