Effects of fosfomycin and imipenem/cilastatin on nephrotoxicity and renal excretion of vancomycin in rats.
OBJECTIVE
The effects of fosfomycin and imipenem/cilastatin on the nephrotoxicity of vancomycin were studied in rats, and those on the renal handling of vancomycin were also investigated in perfused kidneys.


METHODS
The protective effects of fosfomycin and imipenem/cilastatin on vancomycin nephrotoxicity were evaluated by increases in plasma concentration of creatinine and urea nitrogen in rats. The urinary excretion of vancomycin was measured and analyzed kinetically in the perfused rat kidney.


RESULTS
The nephrotoxicity induced by vancomycin (500 mg/kg, i.v.) was inhibited almost completely by co-administration of fosfomycin or imipenem/cilastatin. In the perfused rat kidney, the excretion ratio of vancomycin was less than those of p-aminohippurate and cimetidine, and greater than that of arbekacin, suggesting the secretion and reabsorption of vancomycin in renal tubules. The tissue/perfusate ratios of unbound vancomycin were not significantly changed by co-treatment with fosfomycin or imipenem/cilastatin. Imipenem/cilastatin significantly decreased the excretion ratio of vancomycin. Fosfomycin also decreased vancomycin excretion ratio, although this effect was not significant.


CONCLUSIONS
The renal handling of vancomycin was different from those of organic anions and cations and an aminoglycoside antibiotic. The protective effects of fosfomycin and imipenem/cilastatin against the nephrotoxicity of vancomycin might be partly due to the change in renal handling of vancomycin, probably in its tubular secretion/ reabsorption, in rats.
Nakamura
T
T
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Japan.
Hashimoto
Y
Y
Kokuryo
T
T
Inui
K I
KI
D000818:Animals; D015377:Cilastatin / Q000494:pharmacology; D000077728:Cilastatin, Imipenem Drug Combination; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000493:pharmacokinetics / Q000494:pharmacology*; D005578:Fosfomycin / Q000494:pharmacology*; D015378:Imipenem / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017208:Rats, Wistar; D014640:Vancomycin / Q000378:metabolism* / Q000494:pharmacology
D004338:Drug Combinations; D015377:Cilastatin; D005578:Fosfomycin; D014640:Vancomycin; D015378:Imipenem; D000077728:Cilastatin, Imipenem Drug Combination