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

Abstract

The concept of altered biologic behavior of administered radiopharmaceuticals is used routinely in clinical nuclear medicine to increase the sensitivity of diagnosis, monitor the efficacy of chemotherapeutic drugs and radiation treatment, and determine injury caused by a drug whose effect has exceeded its therapeutic value. In this study, cyclosporine-A (CsA) an immunosuppressant drug known to cause nephrotoxicity due to tubular impairment and Tc- 99m MAG-3, a renal imaging radiopharmaceutical secreted by the tubules have been used in animal models to establish a method for investigating the nephrotoxicity of drugs. New Zealand rabbits and Wistar rats were used. The rabbits 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 studies 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 intravenous bolus injection of 44.4 MBq (1.5 mCi) of Tc-99m MAG-3. 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, killed 3 min later, the kidneys removed and 20 mm frozen sections made. Autoradio-grams were generated from the frozen sections. Creatinine and urea levels were also measured in the rats. There was no consistent difference in creatinine and urea levels between control and CsA treated rabbits and rats. However, for the rabbit, on day 1 or 4 after treatment, there was significant increase in the values of T_max, T_1/2, TTHM and uptake slope between the control and CsA treated animals, indicating intrarenal vasoconstriction and delayed transit of Tc-99m MAG-3 from the parenchyma to the collecting system. 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 concept of altered biologic behavior of Tc-99m MAG-3 can be used effectively as a toxicologic method for studying nephrotoxicity of drugs as exempli-fied by CsA.

Keywords

Tc-99m MAG-3 cyclosporine-A nephrotoxicity toxicologic technique rabbits rats

Get full access to this article

View all access options for this article.

References

Hladik III WB , Nigg KK , Rhodes BA. Drug-induced changes in biological distribution of radiopharmaceuticals . Semin Nucl Med 1982; 12: 184-218 .

Owunwanne A , Patel M , Sadek S. Drug-radiopharmaceutical interactions. In: The Handbook of Radiopharmaceuticals Chapman and Hall Medical, London 1995; pp 43-56.

Shihab-Eldeen A , Owunwanne A , Junaid TA , Yacoub T. Experimental studies on multiorgan toxicity of cyclosporine-A in rats using a radiopharmaceutical and comparison with histological findings . Human Expt Toxicol 1996; 15: 867-871 .

Fine EJ. Intervention in renal scintigraphy . Semin Nucl Med 1991; 21: 116-127 .

Iskandrian AS. Single-photon emission computed tomographic thallium imaging with adenosine, dipyridamole and excerise . Am Heart J 1991; 122: 279-284 .

Valdes Olmos RA , Hoefnagel CA , vander Shoot JB. Nuclear Medicine in the monitoring of organ function and detection of injury related to cancer therapy . Eur J Nucl Med 1993; 20: 515-546 .

Landuyt W et al. Unilateral kidney irradiation and late retreatment with cis-dichlorodiammine-platinum (II): functional measurements with Tc- 99m-dimercaptosuccinic acid . IntJRadiatOncol Biol Phys 1988; 14: 95-101 .

Van Luijk WHJ et al.

Is the relative Tc-99m DMSA clearance a useful maker of proximal tubular dysfunction?

Eur J Nucl Med 1984; 9: 439-442 .

Dhawan RT et al. Contrast nephrotoxicity and the role of radionuclide renal scan . JNuclMed 1996; 37: 1828-1830 .

10.

Murray BM , Paller MS , Ferris TF. Effect of cyclosporine administration on renal hemodynamics in concious rats : Kidney Int 1985; 28: 767-774 .

11.

Whiting PH , Thomson AW , Blair JT , Simpson JG. Experimental cyclosporin A nephrotoxicity . Br J Exp Pathol 1982; 63: 88-94 .

12.

McNally PG , Fechally J. Pathophysiology of cyclosporin A nephrotoxicity: experimental and clinical observations . Nephrol Dial Transplant 1992; 1: 791-804 .

13.

Mihatsch MJ , Thiel G , Ryffel B. Morphologic diagnosis of cyclosporine nephrotoxicity . Semin Diagn Pathol 1988; 5: 104-121 .

14.

Myers BD. Cyclosporine nephrotoxicity . Kidney Int 1986; 30: 964-974 .

15.

Ryffel B , Donatsch P , Madorin M. Toxicological evaluation of cyclosporin . A Arch Toxicol 1983; 53: 107-141 .

16.

Sullivan BA , Hak LJ , Finn WC. Cyclosporine nephrotoxicity: studies in laboratory animals . Transplant Proc 1985; 17: 145-154 .

17.

Fitzberg AR , Kasina S , Eshima D , Johnson DL. Synthesis and biological evaluation of 99mTc MAG-3 as a hippuran replacement . JNuclMed 1986; 27: 111-116 .

18.

Taylor A et al. Technetium-99m MAG-3 kit formulation: preliminary results in normal volunteers and patients with renal failure . JNucl Med 1988; 29: 616-622 .

19.

Klintmalm GPC et al. Tc-99m DTPA and I-131 Hippuran findings in liver transplant recipients treated with cyclosporin A . Radiology 1982; 142: 199-202 .

20.

Prescott MC , Testa HJ , Lawson RS , Johnson RWG. The effect of cyclosporin A on the results of radionuclide investigations of kidney function in renal transplant recipients. In: Constable AR , Brown NJG , Tauxe WN (eds). Radionuclides in Nephrology, Joekes AM. Academic Press, Grune and Stratton, New York , 1987; pp 275-279.

21.

Blair JT et al. Toxicity of the immune suppressant cyclosporin-A in the rat . Pathology 1982; 138: 163-178 .

22.

Skinner R et al. Assessment of chemotherapy associated nephrotoxicity in children with cancer . Cancer Chemother Pharmacol 1991; 28: 81-92 .