The comparative toxicokinetics of oxazepam were studied in F344 rats, B6C3F1 mice, and Swiss-Webster mice of both sexes after an iv dose of 20 mglkg and oral gavage doses of 50, 200, and 400 mglkg. In addition, the toxicokinetics of oxazepam in a 3-week dosedfeed study of male B6C3F1 mice at 125 and 2500 ppm were also investigated. Results indicated that the elimination of oxazepam from plasma after iv injection in both rats and mice were first-order and could be best described by a two-compartment model with a terminal elimination half-life of 4-5 h for rats and 5-7 h for mice. After oral gavage dosing the peak oxazepam plasma concentrations in most rodents were reached within 2-3.5 h. At all doses studied, female rodents had significantly higher plasma concentrations than males. Absorption of oxazepam was significantly extended at higher oral doses of 200 and 400 mg/kg. At 50 mg/kg, the bioavailability of oxazepam in rats (40%) was lower than in Swiss-Webster mice (90%). The bioavailability of oxazepam in both B6C3F1 and Swiss-Webster mice decreased with increasing dose. A dose proportionality of was not observed in rats and mice after gavage doses of 50, 200, and 400 mg/kg. Plasma concentrations of oxazepam in the dosed-feed study increased with the concentration of oxazepam in the feed, a quasi-steady-state of plasma concentrations of oxazepam was reached after approximately 4 days ad libitum exposure.
In B6C3F1 mice, the estimated relative bioavailability of oxazepam from dosed feed (relative to gavage study at 50 mg/kg) was about 43%.
Experimental Section
Chemicals-Oxazepam (lot #86017.01) was procured from Roussell Corp. (New York, NY); the identity and purity were confirmed by independent analyses. Acetophenone, used as an internal standard for oxazepam chromatographic analysis, was obtained from Aldrich Chemical Co. (Milwaukee, WI). Acetonitrile and glacial acetic acid were obtained from Fisher Scientific (Springfield, NJ). Emulphor EL-620 was obtained from GAF (New York, NY).