Effect of Cilastatin on Renal Handling of Vancomycin in Rats

• Published in: Journal of pharmaceutical sciences Vol. 87; no. 9; pp. 1173 - 1176
• Main Authors: Kusama, Makiko, Yamamoto, Koujirou, Yamada, Harumi, Kotaki, Hajime, Sato, Hitoshi, Iga, Tatsuji
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.09.1998; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Animals; Anti-Bacterial Agents - pharmacokinetics; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Biological Availability; Cilastatin - pharmacology; Half-Life; Kidney - drug effects; Kidney - metabolism; Male; Medical sciences; Metabolic Clearance Rate; Pharmacology. Drug treatments; Protease Inhibitors - pharmacology; Protein Binding; Rats; Rats, Wistar; Vancomycin - pharmacokinetics; Glomerular filtration; Intravenous administration; Rat; Toxicity; Vancomycin; Kidney; Blood plasma; Glycopeptide; Drug interaction; Tubular reabsorption; Drug combination; Enzyme; Rodentia; Cilastatin; Elimination; Enzyme inhibitor; Serum protein; Peptidases; Vertebrata; Antibiotic; Biological fixation; Mammalia; Urinary system; Polypeptide; Animal; Hydrolases; Antibacterial agent; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js9801135

□ To provide insights into the possibility of reducing the nephrotoxicity of vancomycin (VCM) by cilastatin, the effect of cilastatin on the renal handling of VCM, as well as on glomerular filtration rate (GFR) and plasma protein binding of VCM, were studied using rats. After a bolus intravenous (iv) dose of VCM (100 mg/kg), concomitant cilastatin administration (100 mg/kg, iv) resulted in a significant increase in the total VCM clearance and significant decrease in the kidney uptake clearance of VCM, defined as kidney VCM concentration vs AUC ratio. Moreover, after a 3-h continuous iv infusion of VCM (18 or 90 mg/h/kg), significant decrease in the kidney uptake clearance of VCM was observed with concomitant cilastatin iv infusion (300 mg/ h/kg). On the other hand, GFR and VCM plasma protein binding did not show any significant change with cilastatin. From the observation that cilastatin decreased the kidney uptake clearance of VCM and enhanced its urinary excretion, it was suggested that cilastatin inhibited the reabsorption of VCM in the renal proximal tubular cells. Thus, it may be possible that cilastatin alleviates the nephrotoxicit. of VCM due to reduced accumulation and accelerated renal excretion of VCM.