Nephrotoxicity of vancomycin and drug interaction study with cilastatin in rabbits

Abstract

The nephrotoxic effects of vancomycin hydrochloride (VCM) and the potential drug-drug interaction with cilastatin sodium (CS) were examined in rabbits. The aim of the study was to measure the possible dose-related suppressive effects or elimination by cilastatin of the adverse reactions generated by vancomycin in the kidneys of rabbits. To clarify the interactions of these two drugs, we examined the nephrotoxicity and pharmacokinetics of VCM in the rabbit when administered alone and when coadministered with CS. VCM administered alone (300 mg/kg of body weight as an intravenous bolus; n = 5) caused typical symptoms of nephrotoxicity, such as increases in serum creatinine and blood urea nitrogen (BUN) levels, as well as morphological changes in the kidneys. A lack of such signs of nephrotoxicity was observed in the groups administered VCM plus CS (i.e., CS at 150 mg/kg plus VCM at 300 mg/kg or CS at 300 mg/kg plus VCM at 300 mg/kg, intravenous bolus; n = 5/group). At a reduced combination ratio of VCM plus CS (4:1 ratio, VCM at 300 mg/kg plus CS at 75 mg/kg, intravenous bolus; n = 5) some symptoms of nephrotoxicity induced by VCM were present, but the degree of this effect was much reduced and was significantly different from preadministration values by only modest increases of the BUN and N-acetyl-beta-D-glucosaminidase levels (P < 0.05). Overall clearance of VCM was accelerated by coadministration of CS and was found to be dose dependent upon CS. No changes in renal function values from the preadministration values were observed for animals receiving CS alone (300 mg/kg, intravenous bolus; n = 3). These results suggest that CS has the ability to reduce or eliminate in a dose-dependent manner the nephrotoxic effects caused by VCM administration in rabbits.