The pharmacokinetics after single intravenous and single and consecutive 2 week oral administration, tissue distribution, in vitro tissue metabolism, stability, blood partition and protein binding of DA-7867, a new oxazolidinone, were evaluated. After intravenous administration at a dose of 10mg/kg to rats, DA-7867 was eliminated slowly with time-averaged total body clearance of 0.915 ml/min/kg. After consecutive 2 week oral administration at a dose of 2 mg/kg/day to rats, DA-7867 was accumulated in rats; the AUC was significantly greater (1430 versus 1880 micro g min/ml) than that after single oral administration at a dose of 2 mg/kg. The rat tissues studied had low affinity to DA-7867; the tissue-to-plasma ratios were smaller than unity after both intravenous and oral administration at a dose of 20 mg/kg. The rat tissues studied had almost negligible metabolic activity for DA-7867 based on 30 min incubation of DA-7867 with 9000 g supernatant fraction of rat tissues. DA-7867 was stable for up to 24 h incubation in various buffer solutions having pHs from 1 to 11, Sørensen phosphate buffer of pH 7.4, and rat plasma, urine and liver homogenate and 3h incubation in five human gastric juices. The binding of DA-7867 to 4% human serum albumin was 50.6% at DA-7867 concentrations ranging from 0.5 to 20 micro g/ml. The equilibrium of DA-7867 between plasma and blood cells of rabbit blood reached fast (within 30 s manual mixing), and the plasma-to-blood cell concentration ratios were independent of initial blood concentrations of DA-7867, 1-20 micro g/ml; the values ranged from 1.39 to 1.63. Protein binding of DA-7867 in five fresh rats plasma was 72.3%.
Copyright 2004 John Wiley & Sons, Ltd.