title: Assessment of oral bioavailability and preclinical pharmacokinetics of DRF-6196, a novel oxazolidinone analogue, in comparison to linezolid.
abstract: The aim of this study was to determine the bioavailability of a novel oxazolidinone, DRF-6196, in mice and rats following intravenous (i.v) and oral dosing and to compare the pharmacokinetics with those obtained following linezolid dosing. Blood samples were drawn at predetermined intervals up to 24 h post-dose after either DRF-6196 or linezolid administration. The concentrations of DRF-6196 and linezolid in various plasma samples were determined by a HPLC method. Following oral administration maximum concentrations of DRF-6196 were achieved within 0.5 h irrespective of the species. While the doses increased in the ratio of 1 : 3 : 10, mean Cmax and AUC(0-infinity) values in mice for DRF-6196 increased in the ratio of 1 : 3.87 : 8.53 and 1 : 2.51 : 9.24, respectively. Both the Cmax and AUC(0-infinity) values increased almost proportional to the dose administered in mice. Following i.v administration, the concentration of DRF-6196 declined in a bi-exponential fashion with terminal elimination half-life of 1.5 h irrespective of the species. The systemic clearance and volume of distribution of DRF-6196 in mice were 1.14 L/h/kg and 0.66 L/kg, respectively after i.v administration, while the respective values in rats were 0.61 L/h/kg and 0.41L/kg, respectively. Elimination half-life ranged between 0.8-1.5 h. Absolute oral bioavailability of DRF-6196 was found to be 80-96% across the test dose range. Although plasma levels of DRF-6196 were lesser compared to linezolid in the initial hours, it may not have any consequences on the clinical effectiveness of the molecule.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Discovery Research, Dr Reddy's Laboratories Ltd, Miyapur, Hyderabad, India.
authors.forename: Ravikanth
authors.initials: R
authors.lastname: Bhamidipati
authors.forename: P
authors.initials: P
authors.lastname: Venkatesh
authors.forename: Prajakta V
authors.initials: PV
authors.lastname: Dravid
authors.forename: Prasad C
authors.initials: PC
authors.lastname: Narasimhulu
authors.forename: Sastry
authors.initials: S
authors.lastname: Tvrs
authors.forename: Jagattaran
authors.initials: J
authors.lastname: Das
authors.forename: Ramesh
authors.initials: R
authors.lastname: Mullangi
authors.forename: Nuggehally R
authors.initials: NR
authors.lastname: Srinivas
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D052176:Azulenes; D001682:Biological Availability; D000069349:Linezolid; D008297:Male; D051379:Mice; D023303:Oxazolidinones / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D052176:Azulenes; C501045:N-(3-(4H,6H-5-oxa-10b-aza-benzo(e)azulen-8-yl)-2-oxo-oxazolidin-5(S)-ylmethyl)acetamide; D023303:Oxazolidinones; D000069349:Linezolid