Cisplatin is a heavy metal complex considered to be a first-line therapeutic drug for the treatment of solid tumors to the testes and ovary. The proposed research is directed toward better defining the manner in which this drug interacts with the kidney. This is important not only because the urine is the principal route of elimination but also because the major dose-limiting side effect of cisplatin is renal tubule damage leading to kidney failure. The proposed research will utilize an in vivo animal model which takes advantage of the fact that the tubules of each kidney in birds are supplied separately with blood via a venous portal system in addition to the normal arterial supply. This allows administration of cisplatin directly into the peritubular circulation of one kidney in a manner that cannot be done in a mammal. The experiments will test the hypothesis that cisplatin itself enters the tubule cells from blood in peritubular capillaries. After baseline function of the two kidneys has been assessed, cisplatin will be injected into one portal circulation, and the function tests repeated at intervals. Unilateral damage of the injected side kidney would support the hypothesis. The possibility that uptake inhibitors protect the kidney from the toxic effects of cisplatin will be examined by pretreating chickens with the potential protecting agents prior to administration of cisplatin. The proposed research will also determine the extent of in vivo renal tubular secretion and biotransformation of cisplatin during infusion of low amounts of the drug into one renal portal circulation. Platinum species in urine and kidney tissue will be identified and quantified by a combination of high-pressure liquid chromatography and atomic absorption spectroscopy. By comparing the identity and quantity of total platinum and individual metabolites in urine from the infused and non-infused kidneys, the method will allow an estimate of excretory transport of cisplatin, the amount retained in the kidney, and the extent of its metabolism by the kidney cells. The results should provide information beneficial not only to the use of cisplatin, but also to the development of less toxic platinum complexes and to the optimization of conditions for their clinical use.
