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Abstract
The relative effects of pretreatment with allyl alcohol and carbon tetrachloride on
oxidative and glucuronide metabolism of lorazepam have been compared in the isolated
perfused rat liver. Livers from rats pretreated for 24 hr with allyl alcohol (1.8
ml/kg, 1:50 solution, to induce pericentral hepatic necrosis), carbon tetrachloride
(0.8 mg/kg in corn oil, to induce perivenular hepatic necrosis), or vehicle were perfused
with 20% rat blood, 80% Krebs bicarbonate buffer at 20 ml/min. After 300 μg of lorazepam
had been added to the reservoir, perfusate concentrations of lorazepam were measured
in the perfusate at timed intervals. After 180 min, lorazepam and lorazepam glucuronide
were measured in perfusate, bile, and liver homogenate. Allyl alcohol and carbon tetrachloride
lowered lorazepam clearance by 47% and 77%, respectively. Recovery of lorzaepam glucuronide
after 180 min was lowered by 35% by treatment with allyl alcohol and increased 73%
by treatment with carbon tetrachloride. Glucuronide recovery permitted estimation
of fractional glucuronide vs. nonglucuronide clearance. In control rats, glucuronide
clearance accounted for 25% of total clearance. Allyl alcohol caused a 64% reduction
in glucuronide clearance but only a 39% reduction in nonglucuronide clearance. In
contrast, carbon tetrachloride caused a 60% reduction in glucuronide clearance but
an 83% reduction in nonglucuronide clearance. The differences in ratios of the changes
in glucuronide and nonglucuronide clearance provide further circumstantial evidence
that is consistent with the hypothesis of predominant periportal localization of glucuronidation
and pericentral localization of oxidative metabolism of lorazepam.
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Article info
Publication history
Accepted:
July 26,
1983
Received:
January 7,
1983
Footnotes
☆This work is supported by NIH grants GM 31304 and AA00267 and by the Veteran's Administration.
Identification
Copyright
© 1983 Published by Elsevier Inc.
