Nephrotoxicity of dactimicin, a novel pseudo-disaccharide aminoglycoside possessing the N-formimidoyl group, compared with that of astromicin, amikacin and other aminoglycoside antibiotics in animals.

The nephrotoxicity of dactimicin, the first aminoglycoside possessing the N-formimidoyl group, was compared with that of astromicin and, in part, amikacin, ribostamycin, kanamycin and gentamicin as reference aminoglycoside antibiotics. When a dose of 200 mg/kg was given intramuscularly to dehydrated mice, dactimicin caused no change of BUN and serum creatinine, while reference aminoglycosides caused significant elevations of the parameters. In the urinalysis of rats at doses of 40 and 80 mg/kg per day for 11 days or 21 days, dactimicin caused little changes in urinary parameters except for nucleated cells and NAG. In a detailed comparison between dactimicin and astromicin at 20, 40, 80, 120, 180 and 270 mg/kg for 11 or 30 days, dactimicin induced fewer changes in nucleated cells and NAG at high dosages. While dactimicin and astromicin caused no significant changes in BUN and serum creatinine at dosages of 20-270 mg/kg, histological observations using light and electron microscopes revealed that dactimicin consistently showed fewer lesions on the proximal tubular cells than those of astromicin for all dosages. When injected intramuscularly in rats, dactimicin and astromicin showed a similar distribution in the blood and main organs, except for the kidney, in which renal accumulation of dactimicin was about 60% of that of astromicin. Dactimicin slowly degraded in vitro and in vivo to give fortimicin B as a main product which was accumulated in the kidney. Through comparative studies with astromicin, it was disclosed that the N-formimidoyl group of dactimicin did not increase but decreased the nephrotoxicity, probably by suppressing reabsorption of dactimicin via proximal tubular cells.