Pharmacokinetics and metabolism of miloxacin in cultured eel

Miloxacin (5,8-dihydro-5-methoxy-8-oxo-2 H-1,3-dioxolo-[4,5-g]quinoline-7-c arboxylic acid) is a synthetic antibacterial agent and is regulated in conf ormity with the Pharmaceutical Law in Japan. The pharmacokinetics and metab olism 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 t his study. The kinetics of miloxacin was described by a two-compartment mod el after intravascular administration. The distribution half-life (T-1/2 al pha = 0.86 h) of miloxacin was shorter than the elimination half-life (T-1/ 2 beta = 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 (T-1/2 = 34.7 h) after oral dosing. The bioavailabil ity was calculated to be 87.9%. The tissue levels of miloxacin reached thei r peak levels within 1 day after oral administration. At their highest leve ls, 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-dio xolo-[4,5-g]quinoline-7-carboxylic acid (M-1) and the glucuronic acid conju gate of miloxacin and M-1 were detected, and a large amount of M-1 was stil l observed in bile at 20 days post dosing. As an application of pharmacokin etics, we attempted to evaluate the Japanese dosage regimens of miloxacin i n cultured eel. A curve for predicting miloxacin levels was obtained by a c omputerized calculation, using various pharmacokinetics parameters that wer e experimentally determined. The curve was coincident with drug levels duri ng the actual multiple oral dosing (60 mg/kg body weight) in this experimen t. The serum levels of miloxacin were maintained above the MIC (for Edwards iella tarda, 0.1 mug/ml). However, this seems to be a considerably excessiv e dosing because of the high value of the average steady-state serum concen tration (Css: 55.4 mug/ml). (C) 2001 Elsevier Science B.V. All rights reser ved.