First pass conjugation and enterohepatic recycling of oxazepam in dogs; intravenous tolerance of oxazepam in propylene glycol.

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 When bile was withdrawn the elimination of oxazepam was more rapid with an increase of apparent plasma clearance.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.