Effect of phenobarbital on cephaloridine toxicity and accumulation in rabbit and rat kidneys

Cephaloridine causes necrosis of renal proximal tubules in humans and laboratory animals. This antibiotic nephrotoxicity in rats has been shown to be reduced by mixed-function oxidase (MFO) inhibitors such as piperonyl butoxide and cobaltous chloride. The purpose of this study was to determine the effect of phenobarbital, a MFO inducer, on cephaloridine nephrotoxicity in rats and rabbits. Phenobarbital induced rabbit renal MFO activities and also potentiated cephaloridine toxicity in rabbit kidneys. In contrast, a similar treatment with phenobarbital produced little effect on rat renal MFO activities and did not alter cephaloridine nephrotoxicity in rats. These results suggested that cephaloridine may have to be bioactivated within the kidney prior to producing toxicity. However, a higher renal cortical concentration of cephaloridine was detected in phenobarbital-treated rabbits. This higher concentration appeared to be due to a greater ability of renal cortical cells to accumulate cephaloridine. Therefore, rather than as a result of enzyme induction, the potentiating effect of phenobarbital on cephaloridine nephrotoxicity might be due to the increased renal cortical accumulation of the parent drug, cephaloridine.