The use of radiopharmaceuticals as an effective toxicologic technique for studying nephrotoxicity of drugs: cyclosporine-A

The concept of altered biologic behavior of administered radiopharmaceutica ls is used routinely in clinical nuclear medicine to increase the sensitivi ty of diagnosis, monitor the efficacy of chemotherapeutic drugs and radiati on treatment, and determine injury caused by a drug whose effect has exceed ed its therapeutic value. In this study, cyclosporine-A (CsA) an immunosupp ressant drug known to cause nephrotoxicity due to tubular impairment and Tc -99m MAG-3, a renal imaging radiopharmaceutical secreted by the tubules hav e been used in animal models to establish a method for investigating the ne phrotoxicity of drugs. New Zealand rabbits and Wistar rats were used. The r abbits and rats were treated with 30 mg/kg of CsA for 4 and 28 consecutive days respectively. Plasma creatinine and urea were measured and renogram st udies were performed in the rabbits prior to and on 1, 4, 8, 11 and 15 days after treatment with CsA. For the renogram, the rabbits were given an intr avenous bolus injection of 44.4 MBq (1.5 mCi) of Tc-99m MAG3. The T-max T-1 /2, TTHM and uptake slope of the Tc-99m MAG-3 were calculated. Each rat was injected intravenously with 185 MBq (5 mCi) of Tc-99m MAG-3, k illed 3 min later, the kidneys removed and 28 mm frozen sections made. Auto radiograms were generated from the frozen sections. Creatinine and urea lev els were also measured in the rats. There was no consistent difference in c reatinine and urea levels between control and CsA treated rabbits and rats. However, for the rabbit, on day 1 or 4 after treatment, there was signific ant increase in the values of T-max, T-1/2 TTHM and uptake slope between th e control and CsA treated animals, indicating intrarenal vasoconstriction a nd delayed transit of Tc-99m MAG-3 from the parenchyma to the collecting sy stem. This delay is dramatically shown in the tissue autoradiograms of the rats. The results are consistent with reported nephrotoxicity of CsA using other techniques. The results of this study, therefore, indicate that the c oncept of altered biologic behavior of Tc-99m MAG-3 can be used effectively as a toxicologic method for studying nephrotoxicity of drugs as exemplifie d by CsA.