Hepatic and extrahepatic glucuronidation of lorazepam in the dog

Abstract

The pharmacokinetic disposition of lorazepam was investigated in sham‐operated anesthetized dogs, dogs with hepatic devascularization, and dogs with total splanchnic devascularization following i.v. administration of 0.3 mg per kg of the drug. In sham‐operated dogs, lorazepam distribution was extensive (100 ± 15.2 liters) and clearance approximated expected liver blood flow (971 ± 91 ml per min). Lorazepam glucuronide levels in plasma rose rapidly in the first hour and reached a plateau by 5 hr. Urinary recovery of the conjugate in 5 hr was 45% of administered dose. Hepatic devascularization resulted in 39% reduction in distribution volume, and 89% reduction in clearance; however, there was ..