Effect of hyperthermia on cisplatin pharmacokinetics in normal dogs.
In vitro and in vivo cisplatin pharmacokinetic studies were conducted at 37 degrees C and 42-43 degrees C in dogs. Cisplatin at 1, 2, 3, 4 and 5 micrograms/ml was incubated with canine serum at 37 degrees and 43 degrees C. Aliquots were processed immediately for atomic absorption spectrophotometry to determine total as well as free, ultrafilterable cisplatin concentrations. Thirteen healthy, average-sized mongrel dogs received 1 mg/kg cisplatin as an intravenous bolus. Four were maintained unanaesthetized at 37 degrees C, two were anaesthetized and maintained at 37 degrees C and seven were anaesthetized and maintained at a rectal temperature of 42 degrees C for 60 min. Serum samples were obtained and processed for free and total cisplatin. There were no detectable concentration effects present in either in vitro group. The rate constant reflecting the decay of free cisplatin at 37 degrees C was 0.0035 +/- 0.0007 min-1 and increased significantly (P less than 0.0001) to 0.0053 +/- 0.001 min-1 at 43 degrees C. In vivo pharmacokinetic analysis consisted of model-independent parameters (total body clearance, volume of distribution, half-life and mean residence time). A significant increase (P less than or equal to 0.05) in all parameters was observed with free-cisplatin at 42 degrees C. This data would indicate that at the elevated temperatures encountered in whole body hyperthermia, the rate of formation of reactive metabolites from parent cisplatin is increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Riviere, JE; Page, RL; Dewhirst, MW; Tyczkowska, K; Thrall, DE
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