Nephrotoxicity cephalothin

Figure 7.34 The structures of the two cephalosporin antibiotics. Cephaloridine is nephrotoxic, cephalothin is not.

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. 

Also, there is some correlation between accumulation and nephrotoxicity. For example, neonatal rabbits lacking a developed OAT 1 are less susceptible to the nephrotoxic effects of the drug. Similar drugs, such as cephalothin (Fig. 7.34), lacking the pyridine ring and, so, not cationic, are not nephrotoxic and do not accumulate (Table 7.7). This accumulation of cephaloridine is presumed to be due to the cationic group reducing efflux. 

Cabanillas F, Burgos RC, Rodriguez C, Baldizon C. Nephrotoxicity of combined cephalothin-gentamicin regimen. Arch Intern Med 1975 135(6) 850-2. 

Simpson IJ. Nephrotoxicity and acute renal failure associated with cephalothin and cephaloridine. NZ Med J 1971 74(474) 312-15. 

Beta-lactams such as cephaloridine, cephalothin, cefotiam 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-lactam 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 dihy drothiazine ring which may impart nephrotoxic potential [10]. Clinical and animal studies carried... 

However, the acetoxymethyl side chain in position 3 of the cephem ring may confer nephrotoxic potential as in the case of cephaloglycin [11] and cephalothin [43] but not with cefotaxime (Figure 2) [26]. It is likely that the presence of D-phenylglycyl side chain in the cephaloglycin molecule and its global molecular... 

More interesting, the presence of the thiophene ring in position 7 of the cephem nucleus (Figure 2) has been associated with nephrotoxic effects in the case of cephaloridine and cephalothin and to a lesser extent in the case of the cephamycin cefoxitin [26, 66]. When compared to cephalothin, small alterations of the cefoxitin molecule in positions 3 and 7 of the cephem nucleus, such as replacement of the methyl group with... 

Desacetylation of cephalosporins occurs in liver and kidney via the activity of acetylesterases. Desacetylated cephalosporins all maintain some antibacterial activity. Desacetylcefotaxime penetrates well extra vascular body sites, achieves high tissue concentrations and acts synergistically with cefotaxime [94,95]. Desacetylation of cephaloglycin, cephalothin and cephapiiin resulted in formation of less active desacetyl forms [94] and less toxicity [64]. About 50% of cephaloglycin is metabolized to desacetylcephloglycin, which is less nephrotoxic at... 

The combination of cephalothin wifh an aminoglycoside was more nephrotoxic than methicillin plus aminoglycoside [143]. There is good evidence that concurrent administration of cephalothin and gentamicin are additive nephrotoxins in humans, especially in patients over 60 years of age as wells as in rabbits [144], and renal injuries are intensified in the presence of mild renal ischemia or endotoxemia [108]. The results of prospective randomized comparative studies of the combination mezlocillin/cefotaxime versus gentamicin/cefoxitin showed that the concurrent administration of mezlocillin/cefotaxime has low renal toxicity and can be recommended for the rational and empirical treatment of serious systemic infections [145]. 

Tune BM, Hsu C-H, Fravert D. Cephalothin and carbacephem nephrotoxicity. Role of tubular cell uptake and acylating potential. Biochem Pharmacol 1996 51 557-561. 

Wade JC, Smith CR, Petty BG, Lipsky JJ, Conrad G, Ellner J, Lietman PS. Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus and aminoglycoside. Lancet 1978 3 604-606. 

The combination of cephalothin with an aminoglycoside was more nephrotoxic than methicillin plus... 

Salem PA Jabboury KW, Khalil MF. Severe nephrotoxicity a probable conplication of cis-dichlorodiammineplatinum (II) and cephalothin-gentamicin therapy. Oncology (1982) 39,... 

Boyd JF, Butcher BT, Stewart GT (1973) The nephrotoxic effect of cephaloridine and its polymers. Int J Clin Pharmacol Biopharm 7 307 Brandriss MW, Smith JW, Steinman HG (1965) Common antigenic determinants of penicillin G, cephalothin and 6-aminopenicillanic acid in rabbits. J Immunol 94 696 Bredt J (1965) Akute nicht-allergische Reaktionen bei Anwendung von Depot-Penicillin. Dtsch Med Wochenschr 90 1559... 

M. Mork-Hansen and K. Kaaber, Nephrotoxicity in Combined Cephalothin and Gentamicin Therapy, Acta. Med. Scand. 201, 463 67 (1977). 

The majority of the recent reports on adverse reactions to cephalosporins pertain to nephrotoxic effects (acute renal failure, tubular necrosis) after high dosages (8—24 g/day) of cephalothin, especially in elderly patients with a pre-existing renal insufficiency (44 —47 ). Acute interstitial nephritis with haematuria, eosinophilia, oliguria and azotaemia developed in a 56-year-old woman after 9 days of treatment with 16g of cephalothin per day. The pa-... 

Pasternak, D. P. and Stephens, B. G. (1975) Reversible nephrotoxicity associated with cephalothin therapy. ArcJi. intern. Med., 135, 599. 

---