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The pharmacokinetics of oxazepam was studied in healthy volunteers. When oral doses of 15 mg were given to eight subjects on two occasions 2.5 years apart the individual areas under the plasma concentration time curves did not differ significantly. Plasma clearance ranged between 0.050 and 0.171 x kg-1 x h-1 and half-lives from 5.9 to 25 hours. The urinary recovery of oxazepam conjugates was 67 +/- 15 S.D.% of the dose given and the total recovery including faecal oxazepam was 70 +/- 15 S.D. %. On multiple dosing (5 mg t.i.d.) stable steady-state concentrations were established. There was a tendency for slightly lower steady-state concentrations than predicted from single oral doses. During steady-state 86 +/- 17 S.D. % of the dose was recovered in the urine over a 24 hour period.

Oxazepam dissolved in propylene glycol was administered intravenously to dogs. There were no cardiac or general adverse effects. Hemolysis and thrombophlebitis were observed after rapid infusion (5.6 ml in 1 minute), and were shown to be due to the properties of the vehicle. Comparison of plasma concentration time curves after oral and intravenous administration indicated a bioavailability of 70 +/- 15 S.D. %. The decreased availability after oral dose was considered to be due to first pass elimination as the urinary recovery of metabolites was the same after the two routes of administration. This also indicates complete absorption. In a dog with a chronic biliary fistula 15 mg of oxazepam was given intravenously on two occasions. When normal bile flow into the gut was permitted the disposition of oxazepam was similar to that in normal dogs. When bile was withdrawn the elimination of oxazepam was more rapid with an increase of apparent plasma clearance. In this case 32% of the dose was excreted as conjugates in the bile within 3 hours after administration. In the normal dogs 2-20% of the dose given was recovered in the faeces as the parent compound and practically no conjugates were found. These findings indicate enteral hydrolysis of the conjugates, and a marked enterohepatic recycling or oxazepam.

Three benzodiazepines in equipotent doses: oxazepam 15 mg, dipotassium chlorazepate 10 mg and diazepam 5 mg, were administered in single, oral doses to seven healthy volunteers in a three-way cross-over study. The serum concentrations of oxazepam, N-desmethyldiazepam and diazepam were followed for 72 hours by gas chromatography and electron capture detection. The absorption of diazepam was most rapid and the mean time required to reach peak serum concentration was 45 minutes, followed by N-desmethyldiazepam 80 minutes and oxazepam 114 minutes. The serum concentration decay curves were biphasic with terminal mean half-lives of 48, 62 and 11 hours for diazepam, N-desmethyldiazepam and oxazepam, respectively. The mean and individual serum concentration time data were fitted to a two-compartment open model with first order absorption using a non linear least square program. The mean serum data fitted the model well. The same rank order was obtained with mean absorption half-lives as when comparing mean peak times while slightly shorter terminal half-lives were obtained in the curve fitting of mean serum data. Due to irregularities in the serum concentration time curves only five out of the 21 sets of individual data could satisfy the convergence criterion. The obtained parameters in the curve fitting were also accompanied with very large asymptotic standard deviations.

The pharmacokinetics of oxazepam was investigated in 13 uremic patients. The apparent terminal half-life of oxazepam in plasma was 24-91 hours compared to 5.9-25 hours reported elsewhere for healthy volunteers. The plasma concentrations showed secondary peaks about 24 hours after the dose and this probably gave rise to the increase in half-life. Plasma clearance of oxazepam appeared to be normal. The conjugated metabolites accumulated to concentrations 5-50 times those of the parent compound and could still be detected 5 days after a single oral dose (0.2 mg/kg). Renal clearance of conjugated oxazepam was significantly correlated to creatinine clearance. The urinary recovery over 5 days was 18-57%. The faecal recovery of 3 days was 0.1-19%. In some patients up to 49% of oxazepam in faeces was in the conjugated form. It is concluded that enterohepatic recycling of oxazepam might occur in uremic patients but is not of great quantitative importance. During multiple dosing the accumulation of conjugates was even more pronounced, with plasma concentrations amounting to 14-61 times those of oxazepam. Steady-state plasma concentrations of oxazepam was similar to those obtained in normal subjects.

The effects of prolonged treatment with phenobarbital, diazepam, and oxazepam on behaviour and on the plasma half-life of antipyrine have been studied in the dog. In this species the biotransformation of diazepam and oxazepam is known to be very similar to man. After equipotent doses of phenobarbital (25 mg/kg) and diazepam (35 mg/kg), antipyrine half-life was found to decrease 80 and 40%, respectively, while after treatment with oxazepam (150 mg/kg) there was an increase of 20%. The behavioural effects declined in the dogs during the course of treatment with diazepam but were rather constant during treatment with oxazepam.

Four oxazepam tablet preparations and a suspension of micronized oxazepam in water were given to healthy, fasting volunteers in a comparative bioavailability study using a partial cross-over design. Urinary recovery (0-72 hours) was used as a measure of extent of absorption. Peak serum concentration was used as a measure of rate of absorption. The three dosage forms having the highest dissolution rate in vitro were absorbed to the same extent, while slower dissolving tablets were not as fully absorbed. Peak serum concentration correlated linearly with in vitro dissolution rate. Single oral doses of oxazepam tablets containing 10, 15 and 25 mg showed equal rates and extents of absorption and produced serum concentrations linearly correlated with dose.