Subacute toxicity of cephaloridine to various species

doi:10.1016/0041-008X(66)90051-2

Toxicology and Applied Pharmacology

Volume 8, Issue 3, May 1966, Pages 407-428

https://doi.org/10.1016/0041-008X(66)90051-2 Get rights and content

Abstract

Cephaloridine, an antibiotic derived from cephalosporin C, was administered parenterally for 5 days to rats (1100 mg/kg/day), for 8 weeks to rats and cats, for 12 weeks to dogs (15, 50, or 150 mg/kg/day) and for 8 weeks to rabbits (15, 30, or 45 mg/kg/day). Large daily doses damaged the kidneys of rats, but less than might have been expected from previous studies of single-dose effects. The nephrotoxic effect of cephaloridine also appeared to be noncumulative in rabbits. The kidneys of rabbits and cats were enlarged, but histologic examination did not present evidence of changes attributable to the antibiotic.

Liver weights were increased in rats and cats, but without histologic abnormality. Leukocytopenia occurred in rats and, temporarily, in dogs.

Cephaloridine was not toxic to the rabbit fetus, and toxic doses did not impair the fertility or mating ability of buck rabbits.

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Cited by (41)

Xenobiotic transporters and kidney injury
2017, Advanced Drug Delivery Reviews
Citation Excerpt :
However, cephaloridine remains a classic example of how transport can be a critical determinant of drug-induced renal injury. Single, high doses of cephaloridine lead to proximal tubule necrosis in rats, dogs, and other various laboratory species [244–246]. This injury was prevented by administration of probenecid along with cephaloridine [247].
Renal proximal tubules are targets for toxicity due in part to the expression of transporters that mediate the secretion and reabsorption of xenobiotics. Alterations in transporter expression and/or function can enhance the accumulation of toxicants and sensitize the kidneys to injury. This can be observed when xenobiotic uptake by carrier proteins is increased or efflux of toxicants and their metabolites is reduced. Nephrotoxic chemicals include environmental contaminants (halogenated hydrocarbon solvents, the herbicide paraquat, the fungal toxin ochratoxin, and heavy metals) as well as pharmaceuticals (certain beta-lactam antibiotics, antiviral drugs, and chemotherapeutic drugs). This review explores the mechanisms by which transporters mediate the entry and exit of toxicants from renal tubule cells and influence the degree of kidney injury. Delineating how transport proteins regulate the renal accumulation of toxicants is critical for understanding the likelihood of nephrotoxicity resulting from competition for excretion or genetic polymorphisms that affect transporter function.
Mitochondrial cytochrome c oxidase as a target site for cephalosporin antibiotics in renal epithelial cells (LLC-PK<inf>1</inf>) and renal cortex
2002, Life Sciences
We reported previously that treatment of the pig kidney proximal tubular epithelial cell line LLC-PK₁ with cephaloridine (CLD) decreased the activity of cytochrome c oxidase in the mitochondria of the cells followed by increases in lipid peroxidation and cell necrosis. In this study, we investigated the effects of CLD on the activity of cytochrome c oxidase in mitochondria isolated from LLC-PK₁ cells and purified the enzyme from mitochondria of the rat renal cortex. The activity of cytochrome c oxidase in the isolated mitochondria from LLC-PK₁ cells was significantly decreased from 1 h after addition of 1 mM CLD. Other cephalosporin antibiotics, cefazolin and cefalotin, also decreased the activity of cytochrome c oxidase in the isolated mitochondria. The activity of cytochrome c oxidase purified from the mitochondria of the rat renal cortex was also decreased from 2 h after addition of 1 mM CLD in a non-competitive manner. These results suggest that the direct inhibition of cytochrome c oxidase activity in the mitochondrial electron transport chain by cephlosporins may result from the observed nephrotoxicity.
Cephaloridine-induced inhibition of cytochrome c oxidase activity in the mitochondria of cultured renal epithelial cells (LLC-PK<inf>1</inf>) as a possible mechanism of its nephrotoxicity
2000, Toxicology and Applied Pharmacology
To clarify the mechanism of cephalosporin nephrotoxicity, the effects of cephaloridine (CLD), a nephrotoxic cephalosporin antibiotic, on the mitochondria of the pig kidney proximal tubular epithelial cell line LLC-PK₁ were studied in culture. The activity of cytochrome c oxidase in the mitochondria of LLC-PK₁ cells was significantly decreased from 9 h after addition of 1.0 mM CLD to the cultured cells. These effects were dose-dependent and accompanied with a significant decrease in the ATP content in the cells, followed by marked morphological changes in the mitochondria. These alterations were observed in the treated cells before the increase in lipid peroxidation. The activities of NADH–cytochrome c reductase and succinate dehydrogenase in the mitochondria and NADPH–cytochrome P450 reductase, NADH-cytochrome b₅ reductase, and 7-ethoxycoumarin O-deethylase in the microsomes of the treated cells were not affected. Superoxide anion production by the mitochondria prepared from LLC-PK₁ cells or NADH–cytochrome c reductase was not affected by addition of CLD (1–10 mM), but adriamycin (0.1 mM) or paraquat (0.1 mM) significantly increased the superoxide anion production. These results suggested that the primary action of CLD is inhibition of cytochrome c oxidase activity in the mitochondrial electron transport chain, which decreases intracellular ATP content in renal tubular epithelial cells and that these effects of CLD are followed by increased lipid peroxidation and cellular injury.
Comparison of cephaloridine renal accumulation and urinary excretion between normoglycemic and diabetic animals
1996, Toxicology
The renal toxicity of cephaloridine is reduced in a streptozotocin diabetic rat model. This study tested the hypothesis that renal cortical cephaloridine accumulation was diminished in diabetic rats. The following studies also investigated whether renal excretion was enhanced in diabetic rats. Male Fischer 344 rats were randomly divided into normoglycemic or diabetic groups. Diabetes was induced by injection (intraperitoneal i.p.) of 35 mg/kg streptozotocin. Normoglycemic and diabetic rats were injected (i.p.) with 1500 mg/kg cephaloridine. Peak plasma cephaloridine levels were similar in both groups. Renal cortical accumulation was diminished (P < 0.05) in the diabetic group 1 and 4 h after cephaloridine injection. Urinary cephaloridine excretion was enhanced (P < 0.05) in the diabetic group relative to the normoglycemic animals during the first 4 h after cephaloridine injection. Comparisons between normoglycemic and diabetic groups indicated renal conical cephaloridine accumulation was lower in the diabetic group. These findings would support the hypothesis that reduced cephaloridine toxicity in diabetic animals was due to reduced renal cortical accumulation of the toxin. These data also demonstrate that cephaloridine excretion was enhanced in the diabetic group and may contribute to the diminished renal accumulation.
Cephaloridine nephrotoxicity in diabetic rats: modulation by insulin treatment
1995, Toxicology
Previous studies have indicated that cephaloridine nephrotoxicity was reduced in diabetic rats. This study determined whether the reduction in toxicity was due to streptozotocin or the diabetic state. Male Fischer-344 rats were injected intraperitoneally with 35 mg/kg streptozotocin to induce diabetes. Insulin (5 U/day, subcutaneously) was begun within 72 h and continued for 10 days. Toxicity was quantitated 48 h after injection of cephaloridine (1500 mg/kg i.p.) in normoglycemic (NC), diabetic (DC) and diabetic animals treated with insulin (DIC). Cephaloridine produced diuresis, glucosuria, proteinuria, elevated kidney weight and decreased renal cortical slice accumulation of organic ions in the NC group. Cephaloridine toxicity was reduced in the DC group since kidney weight, BUN level and renal cortical slice accumulation of organic anions were similar between treated and control animals. Cephaloridine treatment of the DIC group was associated with increased BUN levels, proteinuria and diminished renal cortical slice accumulation of organic cations. These results indicated that the diabetic state, and not streptozotocin, reduced cephaloridine nephrotoxicity.
Cephaloridine-induced biochemical changes and cytotoxicity in suspensions of rabbit isolated proximal tubules
1991, Toxicology and Applied Pharmacology
Cephalosporin antibiotics, such as cephaloridine (Cld), are known to be nephrotoxic in vivo and in vitro. In vivo, Cld causes proximal tubule necrosis in rabbits which is preceded by glutathione (GSH) depletion and, under certain conditions, inhibition of mitochondrial function. In vitro, Cld causes GSH depletion, lipid peroxidation, and inhibition of rat kidney slice organic ion uptake. The present investigations were designed to evaluate the temporal relationships of the biochemical “lesions” caused by Cld to the onset of lethal cell injury in suspensions of isolated rabbit proximal tubules. Cld was cytotoxic to suspensions of rabbit proximal tubules (EC50 = 1.10 ± 0.33 mm) in the absence of amino acids (to support GSH synthesis). In this model, Cld also caused GSH and ATP depletion, lipid peroxidation (malondialdehyde formation), and inhibition of tubule respiration. Probenecid prevented Cld accumulation, tubule injury, ATP depletion, and lipid peroxidation and markedly attenuated the GSH depletion. Addition of glycine, cystine, and glutamate to the incubation buffer to support GSH synthesis decreased the tubule accumulation of Cld (due solely to the presence of glutamate) and blocked Cld-induced tubule lethality, lipid peroxidation, ATP depletion, and GSH depletion. Glycine or glutamate alone had no effect on Cld-induced cytotoxicity, whereas cystine was cytoprotective. Buthionine sulfoximine partially reversed the amino acid protection against Cld-induced tubule injury. Thus amino acid-induced protection of tubules from Cld cytotoxicity was due to the combination of a high intracellular GSH content and cytoprotection by cystine. The antioxidant N-N′-diphenyl-p-phenylenediamine (DPPD) blocked tubule injury, ATP depletion, and lipid peroxidation but had no effect on Cld-induced GSH depletion when tubules were incubated for 3 hr. However, when incubations were allowed to run for up to 8 hr, DPPD had no effect on Cld cytoxicity, despite continued inhibition of lipid peroxidation. These data demonstrate that Cld-induced tubule injury in short-term (3 hr) incubations in vitro occurs by a mechanism probably involving lipid peroxidation and occurs only in the absence of amino acids to support GSH synthesis. Inhibition of tubule respiration and ATP depletion could not clearly be causally linked to the onset of cell death in this model. The mechanism of the peroxidation-independent Cld toxicity in tubules incubated for 8 hr or longer is not known at this time.

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Subacute toxicity of cephaloridine to various species

Abstract

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Lancet

Experimental methods used in determining chronic toxicity (a critical review)

Pharmacol. Rev.

Simple method for the rapid determination of serum albumin

Am. J. Clin. Pathol.

Estimation of plasma phosphatase by determination of hydrolysed phenol with amino-antipyrine

J. Clin. Pathol.