Mode of protective action of fosfomycin against dibekacin-induced nephrotoxicity in the dehydrated rats.
We studied the mechanism on protective effect of fosfomycin against experimental nephrotoxicity induced by dibekacin. In order to simplify an experimental model, the dehydrated Wistar rats were used, because a single injection of dibekacin at 30 mg/kg induced acute renal failure in the dehydrated rats, characterized by alteration of urinalytic parameters and BUN values, and retarded elimination of dibekacin from blood. When the rats were administered simultaneously with fosfomycin at 120 mg/kg, the rate of elimination was restored almost to normal, accompanied with improvement of the nephrotoxic parameters. However, markedly accelerated elimination over normal one was not observed, indicating that the improved elimination was not the reason of protection but a result of normal kidney function. On the other hand, fosfomycin protected the proximal tubular lysosomes from the injury of aminoglycoside, as evidenced a) in vivo by suppression of myeloid body formation and protection of lysosomal membrane integrity of the rats treated with dibekacin, and b) in vitro by dose-dependent protection of the lysosomal membrane integrity of the kidney cells. A study of structure-protective activity relation revealed that phosphonate anion possessing an epoxy function was important for protection, and that the mechanism of protection differed from the antibacterial mechanism.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003681:Dehydration / Q000378:metabolism*; D003982:Dibekacin / Q000378:metabolism / Q000633:toxicity*; D005578:Fosfomycin / Q000494:pharmacology*; D066298:In Vitro Techniques; D007612:Kanamycin / Q000031:analogs & derivatives*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D003982:Dibekacin; D007612:Kanamycin