A study of the nephrotoxicity of three cephalosporins in rabbits using 1H NMR spectroscopy
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S Halligan1, S J Byard, A J Spencer
1Department of Toxicology, Sterling Winthrop Pharmaceuticals Research Division, Alnwick, Northumberland, UK.
Abstract:
Male New Zealand White rabbits received a single intravenous injection of 125 mg/kg cephaloridine, 500 mg/kg cefoperazone or 1000 mg/kg cephalothin. Histological examination of kidneys at 48 h post-dose confirmed the presence of bilateral necrosis of the proximal convoluted tubules in the cephaloridine-treated animals. 1H-NMR urinalysis of cephaloridine-treated rabbits detected drug-related resonances, decreased hippurate and increased glucose at 0-24 h post-dose accompanied by elevated levels of lactate, glycine, citrate, glutamine/glutamate and alanine at 24-48 h post-dose. No histopathological changes were observed following administration of cefoperazone or cephalothin. 1H-NMR spectra of urine collected from these animals showed drug-related resonances and decreased hippurate levels at 0-24 h post-dose, and increased glucose levels at 24-48 h post-dose. Analysis of urine by conventional clinical-chemistry failed to reveal any statistically significant differences between the treatment groups. Under the conditions of this study, the nephrotoxic effects of cephaloridine and the minimal effects of cefoperazone and cephalothin could be clearly distinguished by 1H-NMR urinalysis but not by conventional urinalysis.
Insights
1H-NMR urinalysis effectively distinguished cephaloridine nephrotoxicity from minimal effects of cefoperazone and cephalothin in rabbits. Conventional urinalysis failed to detect these differences, highlighting NMR
Area of Science:
- Pharmacology
- Toxicology
- Analytical Chemistry
Background:
- Cephalosporins are widely used antibiotics.
- Assessing antibiotic-induced kidney toxicity is crucial for patient safety.
- Conventional urinalysis may not detect early or subtle nephrotoxic effects.
Purpose of the Study:
- To compare the utility of 1H-NMR urinalysis versus conventional methods in detecting cephalosporin-induced nephrotoxicity.
- To characterize the urinary metabolic profiles associated with different cephalosporins in rabbits.
Main Methods:
- Male New Zealand White rabbits were administered intravenous cephaloridine, cefoperazone, or cephalothin.
- Kidney histology was examined at 48 hours post-dose.
- Urine samples were analyzed using 1H-NMR spectroscopy and conventional clinical-chemistry assays.
Main Results:
- Cephaloridine caused proximal tubule necrosis, while cefoperazone and cephalothin did not.
- 1H-NMR detected drug-related metabolites, decreased hippurate, and altered glucose levels in cephaloridine-treated rabbits.
- Elevated lactate, glycine, citrate, glutamine/glutamate, and alanine were observed 24-48 hours post-cephaloridine.
- Conventional urinalysis showed no significant differences between treatment groups.
Conclusions:
- 1H-NMR urinalysis is a sensitive method for distinguishing cephaloridine-induced nephrotoxicity.
- Conventional urinalysis is insufficient for detecting subtle or early nephrotoxic effects of certain cephalosporins.
- Metabolic profiling via 1H-NMR offers valuable insights into drug-induced kidney injury.