Biliary elimination and hepatic disposition of a new fluoroquinolone, temafloxacin: experimental evaluation.

Abstract

Temafloxacin is a new quinolone derivative presently under evaluation. Its pharmacokinetic profile, and particularly its biliary elimination and hepatic disposition, remains undefined. The present study describes an experimental approach to this issue. Six isolated rabbit liver preparations were perfused for 3h (h) with reconstituted blood in a closed circuit; 10 mg of temafloxacin were added to the circulating blood at the onset of the procedure. Bile was recovered throughout the experiments and liver fragments were taken at the conclusion. Assays were carried out by high-performance liquid chromatography. Pharmacokinetic analysis was performed with reference to a monocompartmental open model. Under these conditions, the serum half-life of temafloxacin was 3.1 and the maximal biliary concentration of 19.3 +/- SEM 3.1 micrograms/ml was reached between 30 and 60 min; the cumulative biliary elimination (0-3 h) amounted to 92 +/- 16 micrograms (0.9% of the added dose). Total and hepatobiliary clearances were calculated as respectively 134 and 2.38 ml/h and the hepatobiliary elimination rate as 0.0042 (h-1). At the end of the procedure, 25.7 +/- 3.5% of the added dose of temafloxacin was still present in the circulating blood, and 13.7 +/- 2.4% in the liver. Degradation of the antibiotic in the perfusion device concerned only 2.4% of the dose. The percentage of temafloxacin undergoing hepatic biotransformation, determined by subtraction, was high (57.3%). Under these experimental conditions, temafloxacin appears to be particularly stable in serum, poorly eliminated as parent compound in the bile, highly fixed in the liver and above all subject to a probable hepatic biotransformation. Extrapolation of these experimental data to other species or to the whole organism would be hazardous, but these results should stimulate studies on a possible hepatic metabolism of this new trifluoroquinolone in man.