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.
Muscle microdialysis has been used to determine the unbound concentrations of the fluoroquinolones, pazufloxacin and ofloxacin, in tissue interstitial fluids (Cisf,u) of rats under steady state conditions. Cisf,u was estimated from the concentration in dialysate and the in-vitro permeability rate constant by the extrapolation method based on the clearance concept. Paper-disks were inserted under the abdominal skin of rats, and the drug concentrations in the fluids penetrating into the disks (Cdisk) were measured and compared with Cisf,u. The Cisf,u of pazufloxacin and ofloxacin in muscle were close to their unbound concentrations in the venous plasma; these were 75.3% and 77.1%, respectively, of the total concentrations in plasma at the steady state. The Cdisk of pazufloxacin and ofloxacin were also close to their Cisf,u. These results indicate that the unbound concentrations of the fluoroquinolones in the tissue interstitial fluids were the same as those in the venous plasma. The disk insertion technique seems to be useful for evaluating drug concentrations in tissue interstitial fluid.
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