Pharmacokinetics and metabolism of miloxacin in cultured eel

Miloxacin (5,8-dihydro-5-methoxy-8-oxo-2H-1,3-dioxolo-[4,5-g] quinoline-7-carboxylic acid) is a synthetic antibacterial agent and is regulated in conformity with the Pharmaceutical Law in Japan. The pharmacokinetics and metabolism of miloxacin after intravascular and oral administration in cultured eel (Anguilla japonica) were examined by using our high-performance liquid chromatography (HPLC) system, which was developed as a reliable and precise method for simultaneous determination of miloxacin and its metabolite in this study. The kinetics of miloxacin was described by a two-compartment model after intravascular administration. The distribution half-life (T1/2alpha = 0.86 h) of miloxacin was shorter than the elimination half-life (T1/2beta = 34.7 h). The kinetics of orally administered miloxacin was fitted to a one-compartment model. Miloxacin was assimilated quickly (T(a1/2) = 3.5 h) and cleared slowly (T1/2 = 34.7 h) after oral dosing. The bioavailability was calculated to be 87.9%. The tissue levels of miloxacin reached their peak levels within 1 day after oral administration. At their highest levels, the concentrations of miloxacin were observed in the order of kidney > muscle > liver. Miloxacin, its main metabolite 5,8-dihydro-8-oxo-2H-1,3-dioxolo-[4,5-g] quinoline-7-carboxylic acid (M-1) and the glucuronic acid conjugate of miloxacin and M-1 were detected, and a large amount of M-1 was still observed in bile at 20 days post dosing. As an application of pharmacokinetics, we attempted to evaluate the Japanese dosage regimens of miloxacin in cultured eel. A curve for predicting miloxacin levels was obtained by a computerized calculation, using various pharmacokinetics parameters that were experimentally determined. The curve was coincident with drug levels during the actual multiple oral dosing (60 mg/kg body weight) in this experiment. The serum levels of miloxacin were maintained above the MIC (for Edwardsiella tarda, 0.1 microgram/ml). However, this seems to be a considerably excessive dosing because of the high value of the average steady-state serum concentration (Css: 55.4 microgram/ml).