Circadian time dependence of cisplatin urinary kinetics

Free platinum urinary excretion kinetics after a 30-min infusion of 60 mg/m2 IV cis-diamminedichloroplatinum (C) were studied during 51 monthly courses of C therapy in 11 patients suffering from a variety of advanced malignancies. Each patient received half of his or her treatment course at 6:00 A.M. and 6:00 P.M. Initial treatment time was randomly assigned and subsequent treatment times were alternated. Each C infusion was accompanied by 4100-ml 5% dextrose and 0.45% NaCl solution given intravenously. Evening C infusion resulted in greater urine output, lower peak urinary platinum concentrations, and lower areas under the curve of cisplatin concentration. While the normal circadian rhythm characteristics of body temperature were not altered by changing the C infusion time, the circadian rhythm characteristics of urine volume 1 mo after treatment were significantly disrupted by morning, but not by evening, C. We conclude: (1) that since the kinetics of certain drugs may be affected by the time of administration, kinetic studies should be performed and reported in a time-qualified fashion, and (2) that it is reasonable to expect that, since kinetic parameters are important in determining drug toxicity and effect, these too may vary predictably during the day.