ABSTRACT
The protective effect of pazufloxacin (PZFX) mesilate, a parenteral quinolone antimicrobial agent, on arbekacin (ABK)-induced nephrotoxicity was evaluated with 8-week-old male Sprague-Dawley rats. Animals were injected with ABK at a dose of 32 mg/kg intramuscularly, or a combination of ABK in the same manner with PZFX mesilate at a dose of 208 mg/kg (160 mg/kg convert to PZFX, active principle of PZFX mesilate) intravenously once a day for 4 days. In consequent, ABK induced increases in protein, beta 2-microglobulin and N-acetyl-beta-(D)-glucosaminidase in urine, and histopathological phospholipidosis in kidneys. The extent of these changes was reduced when ABK was given in a combination with PZFX mesilate. Renal cortex level of ABK increased after an administration of ABK 1 hour to 4 hours; however, the increase was suppressed by coadministration of PZFX mesilate. Taken together, these results suggest that PZFX mesilate has the protective effect on ABK-induced nephrotoxicity, and that this was attributable to a suppression of uptake of ABK in cortical renal tubules.
Subject(s)
Aminoglycosides , Anti-Bacterial Agents/toxicity , Anti-Infective Agents/pharmacology , Dibekacin/analogs & derivatives , Dibekacin/toxicity , Fluoroquinolones , Kidney Diseases/chemically induced , Kidney Diseases/prevention & control , Oxazines/pharmacology , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/therapeutic use , Dibekacin/administration & dosage , Dibekacin/pharmacokinetics , Drug Interactions , Drug Therapy, Combination , Kidney Cortex/metabolism , Kidney Tubules/metabolism , Male , Oxazines/administration & dosage , Oxazines/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
The purpose of this study was to evaluate the distribution of three fluoroquinolones (pazufloxacin, ciprofloxacin and ofloxacin) and a beta-lactam, ceftazidime in the tissue interstitial and intracellular spaces after a single intravenous administration to rats based on muscle microdialysis. The unbound concentration in the tissue interstitial fluid (C(isf,u)) after administration was estimated from the concentration in the dialysate by muscle microdialysis, the in vitro permeability rate constant, and the previously reported effective dialysis coefficient. The C(isf,u)s of pazufloxacin, ciprofloxacin, ofloxacin and ceftazidime in the muscle were close to their unbound concentrations in the venous plasma. These results were consistent with ones previously obtained at steady state. Based on these results, the total concentration in the tissue interstitial fluid (C(isf)) was calculated from the ratio of plasma protein binding, the plasma concentration, and previously reported interstitial-to-plasma albumin ratio in muscle of rats. The calculated C(isf) was compared with the muscle concentration (C(m)) obtained using the homogenized tissue. The C(isf) of ceftazidime was higher than the C(m). The C(isf) of pazufloxacin was found to be almost equal to its C(m). The C(isf)s of ciprofloxacin and ofloxacin were lower than their C(m)s with the exception of the values at 5 min after administration. These results indicate that ceftazidime is mainly distributed in the interstitial space of the muscle, that pazufloxacin is distributed equally in both the interstitial space and the tissue cells, and that ciprofloxacin and ofloxacin are mainly distributed in the tissue cells rather than the interstitial space.
