Nephrotoxicity of an Ellipticine Derivative (N²-Methyl-9-Hydroxyellipticinium Acetate) in Rat: a Defect of Urinary Concentrating Ability

Abstract

The antitumor drug celiptium (N²-methyl-9-hydroxyellipticinium) is an ellipticine derivative effective in experimental tumors and in man. The major side effect is nephrotoxicity. The impairment of renal function is studied in rats following a single i.v. dose of 20 mg/kg celiptium and a long-term study (day 2 to day 60). A loss of body weight is noted in celiptium-treated animals between day 4 and day 15, and recovery occurs between day 15 and day 60. Histologic study shows cortical lesions characterized by focal necrosis of proximal tubules without any glomerular, interstitial, and vascular alterations on day 8. It is to be noted that any medullary lesions were not shown. A polyuria and a decreased creatinine clearance are reported on day 8. We were interested in a special study of this polyuria. For this study, rats were water deprived between day 6 and day 8 following celiptium administration. The decrease of urinary osmolality is not recovered after dehydration and exogenous vasopressin derivative (dD AVP) does not correct the renal concentration defect. AVP plasma levels increase after dehydration. These results suggest a pitressinoresistant urinary concentrating inability in celiptium-treated rats.