Cephaloridine toxicity

Kuo C-H, Hook JB. 1982. Effects of drug-metabolizing enzyme inducers on cephaloridine toxicity in Fischer 344 rats. Toxicology 24 293-303. 

Tune BM, Hsu C-Y, Fravert D. Mechanisms of bacterial endotoxin-cephaloridine toxic synergy and the protective effects of saline infusion in the rabbit kidney. J Pharmacol Exp Ther 1988 244(2) 520-525. 

Tune, B.M., Fravert, D. and Hsu, C.Y. (1989). Oxidative and mitochondrial toxic effects of cephalosporin antibiotics in the kidney A comparative study of cephaloridine and cephaloglycine. Biochem. Pharmacol. 38 795-802. 

Local irritation can produce severe pain after intramuscular injection and thrombophlebitis after intravenous injection. Renal toxicity, including interstitial nephritis and even tubular necrosis, has been demonstrated and has caused the withdrawal of cephaloridine from clinical use. 

These transporters can be responsible for the toxicity of some xenobiotics. For example, the drug cephaloridine is toxic to the kidney as a result of accumulation in the proximal tubular cells, which form the cortex of the kidney. The drug is a substrate for OAT-1 on the basolateral surface and hence is transported into the proximal tubular cells. However, the transport out of these cells from the apical surface into the lumen of the tubule is restricted, probably because of the cationic group on the molecule (Fig. 7.34). The toxicity of cephaloridine is modulated by chemicals that inhibit the OAT-1 and cation transporters. The similar drug cephalothin is not concentrated in the cells and is not nephrotoxic (Table 3.5). See chapter 7 for more details. 

Figure 7.35 The uptake and elimination of cephaloridine by proximal tubular cells in the kidney and possible mechanisms of toxicity. The uptake can be inhibited (probenicid) and the elimination also inhibited (mepiphenidol). Abbreviations OAT 1, organic anion transporter OCT, organic cation transporter ROS, reactive oxygen species.

Metabolic activation via cytochromes P-450 to reactive metabolites. A reactive intermediate has been suggested as some inhibitors of cytochromes P-450 decrease the toxicity, and some inducers of the monooxygenases increase toxicity. However, other inducers and inhibitors do not change toxicity, and these treatments also affect the renal concentration of cephaloridine in a manner consistent with the effect on toxicity. As the p-lactam ring is unstable, a chemical rearrangement to produce a reactive intermediate is also possible. 

Although cephalosporins are more toxic than penicillin, they are well tolerated. Parenteral injection may cause pain when given intramuscularly and may cause thrombophlebitis when given intravenously. The oral cephalosporin administration causes diarrhea by altering the gut ecology. Hypersensitivity reactions are caused and are similar to those of penicillins. Cephaloridine causes nephrotoxicity, but presently available cephalosporins have less renal toxicity. 

However, cortical concentration does not appear to be the sole determinant of toxicity for other cephalosporin antibiotics, since several cephalosporins reach high cortical concentrations without producing nephrotoxicity. For example, both cepha-loglycin and cephaloridine produce nephrotoxicity whereas cephalexin is not nephrotoxic. Cortical concentrations of cephaloridine, cephaloglycin, and cephalexin are approximately equal initially (0-2 hr) following treatment with these antibiotics. While cortical cephaloridine concentration does not decline, cortical concentrations of both cephaloglycin and cephalexin decline in a similar fashion over 3 hr. Thus,... 

In a more recent study, peroxidative and nephrotoxic injuries induced by meropenem and imipenem/ cilastatin in rat and human cortical slices and micro-somes were compared to those induced by cephaloridine [9]. While meropenem and imipenem/cilastatin did produce lipid peroxidation and depressed PAH accumulation and gluconeogenesis in rat and human renal cortex, the effect was substantially less than with cephaloridine [9]. The human renal cortical tissue appears to be less susceptible to p-lactam induced lipid peroxidation than the rat renal cortical tissue with meropenem showed lower renal toxicity then imipenem/cilastatin [9]. 

It has been suggested that mitochondrial injury may mediate, at least in part, the nephrotoxicity of some p-lactams [67]. Mitochondrial respiration with and uptake of succinate after exposure to toxic doses of cephaloridine, cephaloglycin, or imipenem [98] showed significant reduction of both functions. Cephalexin did not affect either the mitochondrial uptake or respiration with succinate. Depressed mi-... 

The results of these studies showed significant inhibition of pahnitoylcarnitine-mediate respiration by cephaloridine in vitro, whereas cephaloglycin, which lacks structural homology with carnitine, caused a greater inhibition of the mitochondrial transport and oxidation of bufyrate than cephaloridine. It is possible that the mitochondrial uptake of butyrate was not affected by cephaloridine maybe because the pyridinyl nitrogen hinders its attack on the monocarboxylate receptors. Cephalexin induced only mild in vitro toxicity to the mitochondrial uptake and oxidation of bufyrate and palmitate [67]. 

Results from animal studies indicate that while furosemide enhanced cephaloridine nephrotoxicity no increased renal toxicity was observed by combining of piperacillin with furosemide [142]. Latamoxef and flo-moxef may decrease nephrotoxicity of vancomycin by inhibiting its uptake into the kidney [146,147]. The results of a retrospective study including renal transplant patients indicate that aztreonam can be safely administered with cyclosporine [148]. Combination therapy with ampicillin/aztreonam in neonates showed a lower renal toxicity than in the group with concurrent administration of oxacillin/ amikacin [149]. 

Comparison of cephaloridine-induced nephrotoxicity in normoglycemic and diabetic rats showed lower renal toxicity in diabetic rats than normoglycemic rats. This is apparently due to the fact that the diabetic renal tissue accumulated less cephaloridine than the tissue from normoglycemic rats [158]. 

Atkinson RM, Curie LP, Prat PAH, Sharpe HM,Tomich EG. Acute toxicity of cephaloridine, an antibiotic derived from cephalosporin C.Toxicol AppI Pharmacol 1966 8(3) 398-406. 

Tune BM, Wu KY, Longerbeam DF, Kempson RE.Transport and toxicity of cephaloridine in the kidney. Effect of furosemide, p-aminohippurate and saline diuresis. J Pharmacol Exp Ther 1977 202(2) 472-478. 

Valentovic M, Ball JG, Rogers BA, Meadows MK, Harmon RC, Moles J. Cephaloridine in vitro toxicity and accumulation in renal slices from normoglycemic and diabetic rats. Fundam AppI Toxicol 1997 38(2) 184-190. 

In addition to inducing AIN, several of the cephalosporins (e.g., cephaloridine, cephaloglycine, cefaclor, and cephalothin) are directly toxic to the proximal tubule. Accumulation in proximal tubular... 

Beta-lactams such as cephaloridine, cephalothin, ce-fotiam and imipenem have been associated with nephrotoxicity in humans and experimental animals [9]. An understanding of their nephrotoxicity mechanisms may provide valuable information for elucidation of the biochemical mechanisms of newer P-Iactam nephrotoxicity. Similarly to cephaloridine, third- generation cephalosporins such as ceftazidime and cefsulodin and fourth-generation cephalosporins such as cefpirome and cefepime possess a quaternary nitrogen attached to the dihydrothiazine ring which may impart nephrotoxic potential [10]. Clinical and animal studies carried out with P-Iactams, such as cephaloglycin, cephaloridine, cephalothin or imipenem, indicated that they show a differential accumulation at the site of their toxicity, the renal cortex [11]. Elucidation of the mechanism of toxic action of these model (i-lactams has become the focus of several research efforts [12-16]. 

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