Chronopharmacology of melatonin in mice to maximize the antitumor effect and minimize the rhythm disturbance effect.
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.
Akagi
Takanori
T
Department of Clinical Pharmacokinetics, Division of Pharmaceutical Science, Graduate School, Kyushu University, Fukuoka, Japan.
Ushinohama
Kazami
K
Ikesue
Shoko
S
Yukawa
Eiji
E
Higuchi
Shun
S
Hamase
Kenji
K
Zaitsu
Kiyoshi
K
Ohdo
Shigehiro
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D002940:Circadian Rhythm / Q000187:drug effects*; D004195:Disease Models, Animal; D004357:Drug Synergism; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000975:Antioxidants; D008550:Melatonin