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Nephrotoxicity of vancomycin and drug interaction study with cilastatin in rabbits
T Toyoguchi1, S Takahashi, J Hosoya
1Department of Pharmacy, Yamagata University Hospital, Japan.
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.
Insights
Cilastatin sodium (CS) reduces vancomycin hydrochloride (VCM)-induced kidney damage in rabbits. This protective effect is dose-dependent, with higher CS doses offering greater protection against VCM nephrotoxicity.
Area of Science:
- Pharmacology
- Nephrology
- Drug Interactions
Background:
- Vancomycin hydrochloride (VCM) is a critical antibiotic, but its use is limited by potential nephrotoxicity.
- Understanding drug interactions is crucial for optimizing therapeutic efficacy and safety.
- Cilastatin sodium (CS) is often coadministered with other drugs, prompting investigation into its potential modulatory effects.
Purpose of the Study:
- To investigate the nephroprotective effects of cilastatin sodium (CS) against vancomycin hydrochloride (VCM)-induced kidney injury in a rabbit model.
- To determine the dose-dependent relationship between CS administration and the mitigation of VCM nephrotoxicity.
- To examine the impact of CS on the pharmacokinetics of VCM.
Main Methods:
- Rabbits were administered VCM alone or in combination with varying doses of CS via intravenous bolus.
- Nephrotoxicity was assessed by monitoring serum creatinine, blood urea nitrogen (BUN), and kidney morphology.
- Pharmacokinetic parameters of VCM, including its clearance, were evaluated in the presence and absence of CS.
Main Results:
- VCM alone induced significant nephrotoxicity, evidenced by elevated creatinine and BUN levels and kidney damage.
- Co-administration of CS with VCM completely abolished VCM-induced nephrotoxicity at higher CS doses (150 and 300 mg/kg).
- At a lower CS dose (75 mg/kg), VCM-induced nephrotoxicity was significantly reduced, with only modest increases in BUN and N-acetyl-beta-D-glucosaminidase.
- CS coadministration accelerated VCM clearance in a dose-dependent manner, and CS alone did not affect renal function.
Conclusions:
- Cilastatin sodium demonstrates significant dose-dependent nephroprotective effects against vancomycin hydrochloride-induced kidney injury in rabbits.
- CS enhances the elimination of VCM, contributing to the reduction of its adverse renal effects.
- These findings suggest a potential therapeutic strategy to mitigate VCM nephrotoxicity through coadministration with CS.