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Nonuniform Alteration of cis-Diamminedichloroplatinum(II) Tissue Distribution in Dogs with Whole Body Hyperthermia¹

College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606 [J. E. R., R. L. P., R. A. R., S. K. C., D. E. T.], and Duke University Medical Center, Durham, North Carolina 27710 [M. W. D.]

The purpose of this study was to investigate the pharmacokinetics and tissue disposition of cisplatin (CDDP) in euthermic and hyperthermic dogs to determine if hyperthermic alteration of tissue CDDP concentration is uniform. Eighteen female beagle dogs received 20, 50, or 80 mg/m² CDDP by constant infusion for 60 min under normothermic or hyperthermic conditions (n = 3/subgroup). Blood, plasma, and ultrafiltered plasma samples were collected during the infusion. At termination of infusion, animals were immediately sacrificed, all major tissues were collected, and platinum levels were determined by atomic absorption spectroscopy. Platinum concentrations in all blood fractions of hyperthermic dogs tended to be lower than those of normothermic dogs. The correlation between dose and blood area under the concentration-time curve was linear at both temperatures. Each tissue concentration was normalized for that individual dog's blood area under the curve. The ratio of relative tissue extraction at 42°C to that at 37°C were compared for each tissue. Values of 1.0 were interpreted as indicating uniform relative tissue extraction at each temperature. Values of >2.0 were obtained in lung and ileum, while values of >1.5 were obtained in liver, adrenal, stomach, colon, duodenum, spleen, and pancreas. Values of <1.0 were obtained in skin and superficial lymph nodes. These results indicate that hyperthermia significantly alters the pattern of CDDP tissue disposition in a nonuniform manner and that pharmacokinetic data obtained at one temperature, e.g., areas under the curve, cannot be used to directly predict tissue concentrations at another temperature.

¹ Supported by Grant CA 42745 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St., Raleigh, NC 27606.

Received 9/11/89. Revised 12/ 7/89.