Pharmacokinetics, blood partition and protein binding of DA‐7867, a new oxazolidinone

Abstract

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%.

Effect of CYP3A1(23) Induction on Clarithromycin Pharmacokinetics in Rats with Diabetes Mellitus

“…. Although the exact reason is not clear, the smaller V ss in rats with DMIS could not be due to a significant decrease in the free (unbound in plasma proteins) fraction of clarithromycin in the rats; the free fractions were 35.2 and 29.4% for rats with DMIS and their controls, respectively, at a clarithromycin concentration of 5 g/ml using an equilibrium dialysis technique (2). Note that body weight gain decreased significantly in rats with DMIA (from 262 to 251 g) and DMIS (from 275 to 263 g) compared to controls (from 260 to 300 g and from 268 to 324 g, respectively) ( Table 2).…”

Effects of water deprivation for 72 hours on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats

“…The spiked dialysis cells were incubated for 24 h in a water-bath shaker kept at 37 8C and at a rate of 50 oscillations per min [20]. The binding of DA-7867 to 4% human serum albumin was 50.6% at DA-7867 concentrations ranging from 0.5 to 20 mg/ml [20]. Hence, the 5 mg/ml was arbitrarily chosen in this plasma protein binding study.…”

“…cutoff of 12 000-14 000; Spectrum Medical Industries) [20]. The spiked dialysis cells were incubated for 24 h in a water-bath shaker kept at 37 8C and at a rate of 50 oscillations per min [20]. The binding of DA-7867 to 4% human serum albumin was 50.6% at DA-7867 concentrations ranging from 0.5 to 20 mg/ml [20].…”

“…On day 4, DA-7867 (dissolved in DMA:PEG 400:distilled water¼3:5:2; v/v/v [7,8,[20][21][22][23][24]) at a dose of 10 mg/kg was injected over 1 min via the jugular vein (total injection volume of approximately 0.6 ml) into the control rats (n ¼ 8) and the rat model of dehydration (n ¼ 13). Water was not supplied during the experimental period in the rat model of dehydration, since this will cause partial rehydration in the rat model of dehydration.…”

“…wt. cutoff of 12 000-14 000; Spectrum Medical Industries) [20]. The spiked dialysis cells were incubated for 24 h in a water-bath shaker kept at 37 8C and at a rate of 50 oscillations per min [20].…”