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Nephrotoxicity of a new cephalosporin, DQ-2556, in rats
Abstract:
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 after 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 min 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 min after dosing commenced. Furthermore, 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.
Insights
A new cephalosporin, DQ-2556, caused kidney damage in rats, specifically proximal tubular necrosis. This injury may be linked to initial constriction of renal arteries following administration.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Cephalosporins are widely used antibiotics.
- Understanding the potential renal toxicity of new drug candidates is crucial for safety.
- DQ-2556 is a novel cephalosporin requiring toxicological evaluation.
Purpose of the Study:
- To investigate the renal toxicity of a single intravenous dose of DQ-2556 in Sprague-Dawley rats.
- To characterize the histological and hemodynamic changes induced by DQ-2556 in the kidney.
- To explore the potential role of renal artery constriction in DQ-2556-induced nephrotoxicity.
Main Methods:
- Administration of DQ-2556 (1200 mg/kg, IV) to rats.
- Histological examination of renal tissues at various time points post-injection.
- Hemodynamic assessment of renal blood flow and vascular resistance.
- Evaluation of the effects of calcium channel blockers on DQ-2556-induced toxicity.
Main Results:
- DQ-2556 induced proximal tubular necrosis and histological changes in renal arteries.
- Early renal artery constriction followed by dilation and vascular wall damage was observed.
- Hemodynamic studies showed transient decreases in renal blood flow and increased vascular resistance.
- Calcium channel blockers significantly attenuated the observed renal injury and biochemical markers (serum urea nitrogen, creatinine).
Conclusions:
- DQ-2556 causes significant nephrotoxicity in rats, characterized by proximal tubular necrosis.
- Renal artery constriction appears to be an early event contributing to the observed tubular damage.
- The findings suggest a potential mechanism involving vascular effects in DQ-2556-induced kidney injury.