Enterohepatic circulation of lorazepam and acetaminophen conjugates in ponies

Adult female ponies (130-225 kg) with chronically implanted external biliary fistulas (T-tubes) participated in three-way cross-over studies using either i.v. lorazepam (10 mg) or acetaminophen (2 g), two model drugs biotransformed mainly by hepatic conjugative reactions. The objectives were to determine the systemic pharmacokinetics, urinary and biliary excretion and degree of enterohepatic circulation (EHC) of these compounds. Trial conditions were: A: EHC intact, with blood and urine, but not bile, collected after i.v. drug administration; B: EHC interrupted, with blood, urine and bile collected after i.v. drug administration; and C: bile infused, EHC open, without i.v. drug administration, with bile collected from trial B (containing biliary excreted drug) infused into the duodenum via the T-tube, followed by collection of blood, urine and bile. At least 2 weeks elapsed between trials. Interruption of the EHC caused lorazepam plasma half-life to shorten (3.4 vs. 2.3 hr with the EHC intact, P less than .1), clearance to increase (9.2 vs. 12.3 ml/min/kg, P less than .1) and total area under the plasma concentration curve for lorazepam glucuronide to decrease (210 vs. 310 ng/ml X hr, P less than .06). Recovery of lorazepam as its glucuronide in bile was 24.5% of the i.v. injected dose. Urinary elimination of lorazepam glucuronide was reduced from 41 to 36% of the dose due to bile collection. Subsequent duodenal infusion of collected bile, containing an average of 2.45 mg of lorazepam as glucuronide, was followed by urinary excretion of 0.48 mg of lorazepam as glucuronide in urine and 0.36 mg re-excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)