© 1992 Oxford University Press
research-article |
Nephrotoxicity of a New Cephalosporin, DQ-2556, in Rats
Drug Safety Research Center, Research Institute, Daitchi Pharmaceutical Co., Ltd.
Received May 8, 1991; accepted October 15, 1991
A single intravenous administration of a new cephalosporin, DQ-2556, at 1200 mg/kg to Sprague-Dawley rats induced proximal tubular necrosis. The histological lesions were not closely correlated with renal cortical concentrations of DQ-2556. Development of renal injuries was examined histologically. The arcuate and cortical radial arteries of the kidneys were constricted immediately alter the injection, but then became dilated and showed histological changes: penetration by erythrocytes, edematous thickening, and necrosis in the media. In addition to congestion in the outer medulla, the proximal convoluted and straight tubules exhibited the earliest changes 30 mm after the injection, namely, enlargement and rounding of the mitochondria and swelling and irregular arrangement of the microvilli in the epithelial cells. Small necrotic foci of epithelium were observed from 4 hr. They were mainly distributed in the outer cortex and the outer stripe of the outer medulla 24 hr later. In the examination of hemodynamics, DQ-2556 significantly decreased the blood flow with increased vascular resistance in the renal artery during and after a single injection. These changes had disappeared wholly or partially 60 mm after dosing commenced. Fur thermore, Ca2+ channel blockers markedly inhibited increases in the serum urea nitrogen and creatinine concentrations and development of the tubular necrosis and the lesions of the arterial walls, which were induced by DQ-2556. These results suggest a possible contribution of the constriction of renal artery to the tubular necrosis.