Relationship between the Transport and Toxicity of Cephalosporins in the Kidney

Abstract

Large doses of cephaloridine cause acute necrosis of the proximal renal tubule that can be prevented by probenecid and other organic anions. Although there is little or no net secretion of cephaloridine by the mammalian kidney, the degree of cephaloridine uptake by the cortex of the rabbit kidney is substantial; this uptake is also prevented by probenecid and other organic anions. Cortical concentrations of cephaloridine were measured in control and probenecid-treated animals of different mammalian species. Evidence of cephaloridine trnsport was found in the guinea pig and the rat as well as in the rabbit. The degree of reduction of cortex-to-serum ratios by probenecid (control cortex-to-serum minus probenecid-treated cortex-to-serum ratios) correlated with the sensitivity to the nephrotoxicity of the drug. This degree or reduction was greatest in the rabbit, intermediate in the guinea pig, and least in the rat. In addition, the newborn rabbit, which is more resistant to the toxicity of cephaloridine than the adult, also had significantly lower cortical concentrations of cephaloridine. Finally, the acute tubular necrosis produced by extremely large doses of cefazolin in the adult rabbit was prevented by probenecid. It was concluded (1) that the nephrotoxicity of cephaloridine is related to its renal cortical transport with high intracellular concentrations of drug; and (2) that this relationship between transport and toxicity exists for cefazolin as well, although the toxicity is of a different order of magnitude. The unusual mechanism of cephaloridine transport in the proximal tubule was contrasted with that of the other cephalosporins in an attempt to explain its greater degree of nephrotoxicity.

Effects of KW-3902, a Novel Adenosine A1-Receptor Antagonist, on Cephaloridine-Induced Acute Renal Failure in Rats

“…In the present study, CER at a dose of 600 mg/kg induced glucosuria, proteinuria and reduction of the glomerular filtration rate (GFR). The reduction in the tubular reabsorption rate of water seems to be due to the reduction of GFR (7,8).…”

“…The decrement by KW-3902 of CER-induced toxicity might be ascribed to a dilution of CER in the proximal tubule due to the diuretic effect of KW-3902, which acts mainly on proximal tubules (18). The decreased concentration of CER in the proximal tubule could result in the attenuated nephrotoxicity of CER, which mainly injures the prox imal tubule (8).…”

“…In fact, it is known that CER-induced renal failure can also be prevented by probenecid and other organic anions (2,3,8). Both the renal cortical transport and the toxicity are prevented by the inhibitors of organic acid secretion, sug gesting that the nephrotoxicity of CER is related to the high intracellular concentration that results from its ac tive transport.…”

“…The main toxic effect of CER has been ascribed to the action of this drug on the proximal tubule (5,6). Suppression of the renal organic anion transport system, reduced glomerular filtration rates, glucosuria, proteinuria, and other effects were ob served following the administration of CER (7)(8)(9). Histopathological studies (5,6,10) demonstrated nuclear pyknosis, cytoplasmic disintegration, hydropic changes and necrosis in the proximal tubular cells and patchy loss of the brushborder membranes in the proximal tubule.…”

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

“…12,13 Some cephalosporins, such as cephaloridine, have severe nephrotoxicity, and it is suggested that their toxic effect is related to the transport systems in the renal proximal tubules. 14 Transport of β-lactam antibiotics mediated by renal organic anion transporter has an important influence on their pharmacokinetics and toxicokinetics. Among human organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8) are PAH/dicarboxylate exchangers, and are localized on the basolateral side of the proximal tubules, whereas OAT4 (SLC22A11) is localized on the apical side of the proximal tubules.…”