Effect of hypertherrnia on cisplatin pharrnacokinetics in normal dogs

Abstract

In vitro and in vivo cisplatin pharmacokinetic studies were conducted at 37°C and 42–43°C in dogs. Cisplatin at 1, 2, 3, 4 and 5 μg/ml was incubated with canine serum at 37° and 43°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°C, two were anaesthetized and maintained at 37°C and seven were anaesthetized and maintained at a rectal temperature of 42°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°C was 0.0035 ± 0.0007 min-1 and increased significantly (P< 0 0001) to 0.0053 ± 0.001 min-1 at 43°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≤0.05) in all parameters was observed with free-cisplatin at 42°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. The increased clearance rate at 42°C of ultrafilterable cisplatin is consistent with increased renal clearance, increased biotransformation, or increased rate of tissue binding. The increased volume of distribution of free cisplation is most compatible with enhanced tissue extraction at 42°C. However, further studies are indicated.