Hepatic and extrahepatic glucuronidation of lorazepam in the dog

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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 still 105 ± 88 ml per min of extrahepatic lorazepam clearance. Five-hour urinary recovery of conjugate decreased by 80%. Total splanchnic devascularization resulted in 37% further reduction in extrahepatic clearance, almost complete inhibition of urinary recovery of conjugate, and further reduction in the volume of distribution. It is concluded that the liver is the major site for lorazepam metabolism in dogs; however, appreciable extrahepatic metabolism occurs, partly in nonhepatic components of the splanchnic organs which act as a reservoir during drug distribution.