Cephalothin toxicity

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. 

These resemble the penicillins structurally, in mode of action and in general lack of toxicity. They are primarily excreted by the kidney by tubular secretion and some also by glomerular filtration (e.g. cephalothin) or only by glomerular filtration (e.g. cefazolin). Cefoperazone is excreted by the bile. Cefotaxime undergoes hepatic biotransformation to active metabolites. Hypersensitivity reactions are qualitatively similar to those of the penicillins, but the epileptogenic potential is less. 

The compound (which had a dihydrothiazine ring fused to the P-lactam core) showed resistance to P-lactamases and was less toxic than benzylpenicillin. The discovery that the basic building block, namely 7-aminocephalosporanic acid (7-ACA), could be synthesised, led to the preparation of numerous cephalosporin derivatives eg cephalothin, cephaloglycin (orally active), cefaclor and cefuroxime (Figure 7). 

Substitutions at position 3 of the dihydrothiazine ring play a major role in the overall pharmacokinetic properties and toxicity. For example, the unusually long half-life of ceftriaxone appears to be caused by the presence of a triazine substituted at this position [62]. Cephalosporins such as cephalothin, cephalogly-cin, cephapirin, cephacetiile and cefotaxime share an acetoxymethyl group at the position 3 (Figure 2) and... 

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]. 

Penicillin-induced renal toxicity is most commonly seen as allergic acute interstitial nephritis (AIN). Methicillin is the most common penicillin to induce AIN, but the use of penicillin G, ampicillin, am-oxacillin, oxacillin, and carbenicillin also can lead to the development of AIN. Typically, acute renal failure follows 1 or 2 weeks of treatment with fever or rashes sometimes occurring before overt renal dysfunction. Removal of the penicillin generally allows renal function to return to normal within a few days or weeks. AIN can also be induced by certain cephalosporins (e.g., cephalothin, cephalexin, cephradine, cefoxitin, cefotaxime) and non-/i-lactam antimicrobials (e.g., sulfonamides, rifampicin, tetracyclines, erythromycin). 

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]. 

Acute tubular necrosis has followed the administration of cephaloridine in doses greater than 4 g/day this agent is no longer available in the U.S. Other cephalosporins, when used by themselves in recommended doses, rarely produce significant renal toxicity. High doses of cephalothin... 

Most instance of drug-induced renal disease are probably due to direct toxicity. Even cephalosporins such as cephalothin or cephaloridin, which can produce immunological reactions, more frequently damage the kidney directly (Parker 1979 a). 

Murray, G. (1974) Toxic paranoid reaction to cephalothin. Drug Intelligence din. Pharm., 8, 71. 

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