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Circadian variation in the susceptibility of male Balb/C mice to ifosfamide.

At each of 6 different timepoints during a single 24-h span, a different subgroup of male Balb/C mice, previously standardized to a 12:12 LD schedule (L from 0600 to 1800) was challenged by one of a series of 5 different dosages of ifosfamide (450, 550, 650, 750 and 850 mg/kg) administered by a single i.p. injection. The measured endpoint of response was the number of deaths per experimental group within 96 h after the administration of the drug. The LD10, LD50 and LD95 (with 95% CL) were calculated by probit analysis. A statistically significant circadian rhythmicity was detected among each of the estimated LD% doses by single cosinor analysis. Male Balb/C mice 5 to 6 weeks of age were most susceptible to the toxic effects of ifosfamide during the middle and late hours of the rest span and most tolerant of the drug during the final hours of the activity span. The acrophase of the best fitting cosine approximation of the dosages required to produce 50% mortality was 03(49), 3 h and 49 min after the midpoint of the daily activity span (00(00)). The experimentally determined LD50's, with 95% CL, ranged from 792 mg/kg (703 mg/kg, 891 mg/kg) at 0500 to 596 mg/kg, (552 mg/kg, 643 mg/kg) at 1700, with a mesor (24-h time series mean) of 694 +/- 14 mg/kg.