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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Hepatic Disposition of the Acyl Glucuronide 1-O-Gemfibrozil-β-d-glucuronide: Effects of Clofibric Acid, Acetaminophen, and Acetaminophen Glucuronide

Lucia Sabordo, Benedetta C. Sallustio, Allan M. Evans and Roger L. Nation
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 44-50;
Lucia Sabordo
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Benedetta C. Sallustio
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Allan M. Evans
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Roger L. Nation
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Abstract

Glucuronidation of carboxylic acid compounds results in the formation of electrophilic acyl glucuronides. Because of their polarity, carrier-mediated hepatic transport systems play an important role in determining both intra- and extrahepatic exposure to these reactive conjugates. We have previously shown that the hepatic membrane transport of 1-O-gemfibrozil-β-d-glucuronide (GG) is carrier-mediated and inhibited by the organic anion dibromosulfophthalein. In this study, we examined the influence of 200 μM acetaminophen, acetaminophen glucuronide, and clofibric acid on the disposition of GG (3 μM) in the recirculating isolated perfused rat liver preparation. GG was taken up by the liver, excreted into bile, and hydrolyzed within the liver to gemfibrozil, which appeared in perfusate but not in bile. Mean ± S.D. hepatic clearance, apparent intrinsic clearance, hepatic extraction ratio, and biliary excretion half-life of GG were 10.4 ± 1.4 ml/min, 94.1 ± 17.9 ml/min, 0.346 ± 0.046, and 30.9 ± 4.9 min, respectively, and approximately 73% of GG was excreted into bile. At the termination of the experiment (t = 90 min), the ratio of GG concentrations in perfusate, liver, and bile was 1:35:3136. Acetaminophen and acetaminophen glucuronide had no effect on the hepatic disposition of GG, suggesting relatively low affinities of acetaminophen conjugates for hepatic transport systems or the involvement of multiple transport systems for glucuronide conjugates. In contrast, clofibric acid increased the hepatic clearance, extraction ratio, and apparent intrinsic clearance of GG (P < .05) while decreasing its biliary excretion half-life (P < .05), suggesting an interaction between GG and hepatically generated clofibric acid glucuronide at the level of hepatic transport. However, the transporter protein(s) involved remains to be identified.

Footnotes

  • Send reprint requests to: Dr. B. C. Sallustio, Department of Clinical Pharmacology, The Queen Elizabeth Hospital, 28 Woodville Rd., Woodville South 5011, South Australia. E-mail:benedetta.sallustio{at}nwahs.sa.gov.au

  • ↵1 This study was supported in part by a National Health and Medical Research Council grant. L.S. is funded by a Queen Elizabeth Hospital Postgraduate Research Scholarship.

  • Abbreviations:
    GG
    1-O-gemfibrozil-β-d-glucuronide
    DBSP
    dibromosulfophthalein
    oatp
    organic anion transporting polypeptide
    mrp
    multidrug resistance-associated protein
    fu
    fraction unbound in perfusate
    CL
    total clearance
    E
    hepatic extraction ratio
    CLint,app
    apparent intrinsic clearance
    t1/2,bile
    biliary excretion half-life
    CLint
    intrinsic clearance
    • Received December 1, 1999.
    • Accepted June 8, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Hepatic Disposition of the Acyl Glucuronide 1-O-Gemfibrozil-β-d-glucuronide: Effects of Clofibric Acid, Acetaminophen, and Acetaminophen Glucuronide

Lucia Sabordo, Benedetta C. Sallustio, Allan M. Evans and Roger L. Nation
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 44-50;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Hepatic Disposition of the Acyl Glucuronide 1-O-Gemfibrozil-β-d-glucuronide: Effects of Clofibric Acid, Acetaminophen, and Acetaminophen Glucuronide

Lucia Sabordo, Benedetta C. Sallustio, Allan M. Evans and Roger L. Nation
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 44-50;
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