CIRCADIAN SYSTEM PHASE-DEPENDENT TOXICITY AND OTHER EFFECTS OF METHOPYRAPONE (SU-4885) IN THE MOUSE

¹ Departments of Pathology and Biochemistry, University of Minnesota Medical School, Minneapolis, Minnesota, and Cambridge State School and Hospital, Cambridge, Minnesota

Blood corticosterone levels in Bagg albino and certain hybrid mice are greatly depressed by 20 mg/kg of methopyrapone (SU-4885) at 20 minutes postinjection. Doses higher than 200 mg/kg produced a general anesthesia and doses from 300 to 400 mg/kg of SU-4885 were lethal in several strains of mice. Moreover, three toxicity experiments, carried out by indirect periodicity analysis, revealed a statistically significant circadian rhythm in the susceptibility of the male C or CD₂D₂ mouse to the early lethal effects of SU-4885.

Under appropriately standardized conditions the number of deaths occurring within 6 hours after the injection of SU-4885 (into separate groups of comparable mice injected at 4-hour intervals during 24-hour periods) depended upon the circadian system phase at the time of drug administration.

The amplitude of this circadian susceptibility-resistance cycle to SU-4885 was large, involving under certain conditions, changes of over 50% around the mean. As to its external timing, the circadian rhythmic increase in susceptibility to methopyrapone occurred prior to the beginning of the daily dark period in mice kept on a regimen of 12 hours of light alternating with 12 hours of darkness. The findings extend the scope of circadian system analysis in the study of respouses to drugs.

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