Original article| Volume 102, ISSUE 5, P805-812, November 1983

Download started.


Periportal localization of lorazepam glucuronidation in the isolated perfused rat liver

      This paper is only available as a PDF. To read, Please Download here.


      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.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Tavassalli M
        • Ozols J
        • Sugionaotto G
        • Cox KH
        • Muller-Eberhard U
        Localization of cytochrome b5 in rat organs and tissues by immuno-chemistry.
        Biochem Biophys Res Commun. 1976; 72: 281
        • Gooding PE
        • Chayen J
        • Sawyer B
        • Slater TF
        Cytochrome P-450 distribution in rat liver and the effect of sodium phenobarbitone administration.
        Chem Biol Interact. 1978; 20: 299
        • Gumucio JJ
        • DeMason LJ
        • Miller DL
        • Krazoski SO
        • Keener M
        Induction of cytochrome P-450 in a selective subpopulation of hepatocytes.
        Am J Physiol. 1978; 234: C102
        • Baron J
        • Redick JA
        • Greenspan P
        • Taira Y
        Immunohistochemical localization of cytochrome c reductase in rat liver.
        Life Sci. 1978; 22: 1097
        • Baron J
        • Redick KA
        • Guengerich FP
        Immunohistochemical localizations of cytochrome P-450 in rat liver.
        Life Sci. 1978; 23: 2627
        • James R
        • Desmond P
        • Kupfer A
        • Schenker S
        • Branch RA
        The differential localization of various drug metabolizing systems within the rat liver lobule as determined by the hepatotoxins allyl alcohol, carbon tetrachloride and bromobenzene.
        J Pharmacol Exp Ther. 1981; 217: 127
        • Schillings TR
        • Sisenwine SF
        • Ruelius HW
        Disposition and metabolism of lorazepam in the male rat.
        Drug Metab Dispos. 1977; 5: 425
        • Evans GH
        • Wilkinson GR
        • Shand DG
        The disposition of propranolol. IV. A dominant role for tissue uptake in the dose-dependent extraction of propranolol by the perfused rat liver.
        J Pharmacol Exp Ther. 1973; 186: 447
        • Wilkinson GR
        • Shand DG
        A physiological approach to hepatic drug clearance (Commentary).
        Clin Pharmacol Ther. 1975; 18: 377
        • Kraus JW
        • Desmond PV
        • Marshall JP
        • Johnson RF
        • Schenker S
        • Wilkinson GR
        The effects of aging and liver disease on the disposition of lorazepam.
        Clin Pharmacol Ther. 1978; 24: 411
        • Rees KR
        • Tarlow JM
        The hepatotoxic action of allyl formate.
        Biochem J. 1967; 104: 757
        • Mitchell JR
        • Nelson SD
        • Thorgiersson SS
        • McMurtry RJ
        • Dybing E
        Metabolic activation: biochemical basis for many drug-induced liver injuries.
        Prog Liver Dis. 1976; 5: 259
        • Brodie BB
        • Reid WD
        • Cho AK
        • Sipes D
        • Krishna G
        • Gillette JR
        Possible mechanism of liver necrosis caused by aromatic organic compounds.
        in: Proc Natl Acad Sci USA. 68. 1971: 160
        • Mitchell JR
        • Jollow DJ
        • Potter WZ
        • Davis DC
        • Gillette JR
        • Brodie BB
        Acetaminophen-induced hepatic necrosis: role of drug metabolism.
        J Pharmacol Exp Ther. 1973; 187: 185
        • Villanuel M
        • Del C
        • De Troanzo EGC
        • Castro JA
        Carbon tetrachloride activation, lipid peroxidation and the mixed function oxygenase activity of various rat tissues.
        Toxicol Appl Pharmacol. 1977; 41: 337
        • Sipes IG
        • Krishna G
        • Gillette JR
        Bioactivation of carbon tetrachloride, chloroform, and bromotrichlormethane: role of cytochrome P-450.
        Life Sci. 1977; 20: 1541
        • Glende Jr, EA
        Carbon tetrachloride induced protection against carbon tetrachloride toxicity.
        Biochem Pharmacol. 1972; 21: 1697
        • Suarez KA
        • Blonsle P
        The relationship of cobaltous chloride induced alterations of hepatic microsomal enzymes to altered carbon tetrachloride hepatoxicity.
        Toxicol Appl Pharmacol. 1976; 37: 23
        • Bengtsson BG
        • Kiessling KH
        • Smith-Kielland A
        • Mørland J
        Partial separation of biochemical characteristics of periportal and perivenous hepatocytes in the liver.
        Eur J Biochem. 1981; 118: 591
        • Desmond PV
        • James R
        • Schenker S
        • Gerkens JF
        • Branch RA
        Preservation of glucuronidation in carbon tetrachloride-induced liver injury in the rat.
        Biochem Pharmacol. 1981; 30: 993
        • Pang S
        • Terrell JA
        Retrograde perfusion to probe the heterogeneous distribution of hepatic drug metabolizing enzymes in rats.
        J Pharmacol Exp Ther. 1981; 216: 339
        • Pang KS
        • Koster H
        • Halsema ICM
        • Scholtens F
        • Mulder GJ
        • Stillwell RN
        Normal and retrograde perfusion to probe the zonal distribution of sulfation and glucuronidation activites of harmol in the perfused rat liver preparation.
        J Pharmacol Exp Ther. 1983; 224: 647