EFFECT OF CILASTATIN ON RENAL HANDLING OF VANCOMYCIN IN RATS

To provide insights into the possibility of reducing the nephrotoxicit y of vancomycin (VCM) by cilastatin, the effect of cilastatin on the r enal handling of VCM, as well as on glomerular filtration rate (GFR) a nd plasma protein binding of VCM, were studied using rats. After a bol us intravenous (iv) dose of VCM (100 mg/kg), concomitant cilastatin ad ministration (100 mg/kg, iv) resulted in a significant increase in the total VCM clearance and significant decrease in the kidney uptake cle arance of VCM, defined as kidney VCM concentration vs AUC ratio. Moreo ver, after a 3-h continuous iv infusion of VCM (18 or 90 mg/h/kg), sig nificant decrease in the kidney uptake clearance of VCM was observed w ith concomitant cilastatin iv infusion (300 mg/h/kg). On the other han d, GFR and VCM plasma protein binding did not show any significant cha nge with cilastatin. From the observation that cilastatin decreased th e kidney uptake clearance of VCM and enhanced its urinary excretion, i t was suggested that cilastatin inhibited the reabsorption of VCM in t he renal proximal tubular cells. Thus, it may be possible that cilasta tin alleviates the nephrotoxicity of VCM due to reduced accumulation a nd accelerated renal excretion of VCM.