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.

In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: Protection by erdosteine

“…Increased urinary NAG excretion demonstrates the cell injury in the renal proximal tubules (Yoshiyama et al, 2001;Oktem et al, 2005;Ozguner et al, 2005). In VCM administrated rats, a significant increase of NAG was demonstrated in different studies (Toyoguchi et al, 1997;Yoshiyama et al, 2001;King and Smith, 2004). In the present study, although glomerular function indicators such as serum Cr and BUN were normal, higher urinary NAG activity was found in VCM-group indicating that VCM might cause an impact in the renal proximal tubule.…”

Cilastatin protection against cyclosporin A-induced nephro­toxicity: clinical evidence

“…Although imipenem could be partially responsible for this effect, this hypothesis seems unlikely since imipenem is known to cause acute proximal tubular necrosis 26 . In contrast, cilastatin has been reported to alleviate the nephrotoxicity of other drugs, such as vancomycin and cisplatin 15,16 . We have previously reported that both cyclosporin and FK506 have a dose-dependent, direct toxic effect on primary cultures of proximal tubules.…”

“…Although cilastatin has also been reported to alleviate the nephrotoxicity of vancomycin and cisplatin in animal models 15,16 , the lack of plausible mechanisms for cilastatin renal protection and the unavailability of pure cilastatin for human use shadowed the potential clinical relevance of cilastatin use. Two recent findings have reactivated interest in this area.…”

Biopsy-proven acute tubular necrosis in a child attributed to vancomycin intoxication

“…Administration of superoxide dismutase reduced the extent of toxic injury. In rabbits, treatment with cilastatin inhibited renal tubular uptake of vancomycin and reduced nephrotoxicity [10]. This reduction of nephrotoxicity has also been demonstrated in humans receiving concomitant treatment with imipenem-cilastatin [11].…”

“…Although the mechanism of nephrotoxicity is unclear, several studies have suggested a direct toxic effect of vancomycin on the renal tubular cells [5,[8][9][10]. Kidney biopsy following vancomycin administration to rabbits has revealed dilation of proximal tubules, destruction of renal tubule cells, swollen mitochondria, increased numbers of vacuoles and lysosomes, and abnormal nuclei [10].…”