FK463 is an inhibitor of 1, 3--D-glucan synthase which is a fungus-specific enzyme for cell wall synthesis, and exhibits potent activity against clinically important pathogenic fungi including Candida species and Aspergillus species. The pharmacokinetics of FK463 were assessed in mice, rats and dogs after intravenous bolus administration at doses of 0.32, 1 and 3.2 mg/kg of FK463 or intravenous 1-h infusion at a dose of 1 mg/kg. Plasma concentration of unchanged drug declined in a bi-phasic way after bolus administration. The pharmacokinetics after bolus administration were in general linear in the dose range of 0.32-3.2 mg/kg in all animals. Total clearance in mice, rats and dogs was respectively in the range of 0.92-1.01, 1.04-1.50 and 0.59-0.78 mL/min/kg, volume of distribution at steady state was 0.38-0.49, 0.42-0.56 and 0.23-0.25 L/kg, and terminal half-life was 5.34-5.71, 3.96-5.05 and 4.24-5.43 h. There were no pharmacokinetic differences between bolus administration and infusion in rats and dogs. The serum protein binding of FK463 was high in all species examined, and was 99.80% in mice, 99.73% in rats and 99.75% in dogs. After bolus administration of 14}C-FK463 into rats and dogs, 14.4 and 15.2% of the radioactivity was recovered in the urine, respectively, while unchanged drug was hardly excreted. In conclusion FK463 showed similar pharmacokinetics in animals across species.
Full conference title:
38th Interscience Conference on Antimicrobial Agents and Chemotherapy
- ICAAC 38th