Pre-clinical assessment of DRF 4367, a novel COX-2 inhibitor: evaluation of pharmacokinetics, absolute oral bioavailability and metabolism in mice and comparative inter-species in vitro metabolism.

The aim of this study was to characterize the pharmacokinetics and determine the absolute bioavailability and metabolism of DRF 4367, a novel COX-2 inhibitor, in mice. In addition, the in vitro metabolism of DRF 4367 was studied in mouse, rat, dog, monkey and human liver microsomes. Following oral administration, maximum concentrations of DRF 4367 were achieved after about 1 h. Upon intravenous (IV) administration, the concentration of DRF 4367 declined in a bi-exponential fashion with a terminal elimination half-life of 4.0 h. The elimination half-life was unchanged with route of administration. The volume of distribution and systemic clearance of DRF 4367 in mice were 0.80 l h(-1) kg(-1) and 0.14 l kg(-1), respectively, after IV administration. The absolute oral bioavailability of DRF 4367 was 44%. In all species of liver microsomes examined, the primary route of metabolism for DRF 4367 was demethylation of benzyl methoxy to form a hydroxy metabolite (M1). The formation of this metabolite was mediated by CYP2D6 and CYP2C19 enzymes. M1 was not found to possess COX-2 inhibitory activity. Chemical-inhibition studies showed that quinidine (selective for CYP2D6) and ticlopidine (selective for CYP2C19) inhibited the formation of the hydroxy metabolite of DRF 4367, whereas potent inhibitors selective for other forms of CYP did not inhibit this oxidative reaction. Upon oral or IV administration of DRF 4367 to mice, unchanged DRF 4367, M1, the O-glucuronide conjugate of M1 (M1-G) and the O-sulfate conjugate of M1 (M1-S) were identified in bile.

Prediction of clinical pharmacokinetic parameters of linezolid using animal data by allometric scaling: applicability for the development of novel oxazolidinones.

1. Allometric scaling has previously been used as an effective tool for the prediction of human pharmacokinetic data. The pharmacokinetic data for linezolid, a novel oxazolidinone to treat Gram-positive pathogens, in mice, rats and dogs were subjected to simple allometric scaling. Generated allometric equations for parameters such as clearance (CL), volume of distribution (Vss) and elimination rate constant (K10) were used to predict human pharmacokinetic parameters including elimination half-lives. In addition, the human plasma concentration-time curve was simulated using a one-compartmental model. 2. Application of simple allometry (Y = aWb) for animal parameters such as CL, Vss, and K10 showed excellent allometric fit (r > or = 0.98). The allometric equations for CL, Vss, and K10 were -0.5465W(0.6595), -0.1369W(0.9246), and -0.4117W(-0.3139), respectively. The confidence in predictability of CL and Vss parameters was particularly high since the allometric exponents of CL and Vss almost approached the suggested values of 0.75 and 1.00, respectively. 3. Animal pharmacokinetic parameters generated in the present authors' laboratories for linezolid were in close agreement with reported literature values. The predicted human values for CL (4.68 l h(-1)), Vss (37.07 litres), and K10 (0.10 h(-1)) were within the range observed for linezolid in the literature (CL = 4-10.5 l h(-1); Vss = 21-53 litres; K10 = 0.09-0.3 h(-1)). The human half-life (t(1/2)) predicted using allometry (6.9 h) was similar to reported values in humans of 5 h. In summary, the retrospective analysis for linezolid suggests that allometric scaling can be used as a prospective tool for predicting human pharmacokinetic parameters of novel oxazolidinones.