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Research ArticleArticle

Evidence for Significant Differences in Microsomal Drug Glucuronidation by Canine and Human Liver and Kidney

Matthew G. Soars, Robert J. Riley, Karen A. B. Findlay, Marcus J. Coffey and Brian Burchell
Drug Metabolism and Disposition February 2001, 29 (2) 121-126;
Matthew G. Soars
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Robert J. Riley
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Karen A. B. Findlay
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Marcus J. Coffey
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Brian Burchell
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Abstract

The in vitro glucuronidation of a range of structurally diverse chemicals has been studied in hepatic and renal microsomes from human donors and the beagle dog. These studies were undertaken to improve on the limited knowledge of glucuronidation by the dog and to assess its suitability as a model species for pharmacokinetic studies. In general, the compounds studied were glucuronidated severalfold more rapidly (based on intrinsic clearance estimates) by DLM than by HLM. Intrinsic clearance values for human UGT1A1 and UGT2B7 substrates were an order of magnitude higher in DLM than in HLM (e.g., gemfibrozil: 31 μl/min/mg versus 3.0 μl/min/mg; ketoprofen: 2.4 μl/min/mg versus 0.2 μl/min/mg). There were also drug-specific differences. HLM readily glucuronidated propofol (2.4 μl/min/mg) whereas DLM appeared unable to glucuronidate this drug directly. Regioselective differences in morphine glucuronidation were also apparent. Human kidney microsomes catalyzed the glucuronidation of many xenobiotics, although glucuronidation of the endobiotic bilirubin was not detectable in this tissue. In direct contrast, dog kidney microsomes glucuronidated bilirubin only (no glucuronidation of all other xenobiotics was detected). These preliminary studies indicated significant differences in the glucuronidation of xenobiotics by microsomes from the livers and kidneys of human and dog and should be confirmed using a larger panel of tissues from individual dogs. Early knowledge of the relative rates of in vitro glucuronidation, the UGTs responsible for drug glucuronidation, and their tissue distribution in different species could assist the design and analysis of preclinical pharmacokinetic and safety evaluation studies.

Footnotes

  • Send reprint requests to: Brian Burchell, Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, Dundee, DD1 9SY, Scotland. E-mail: b.burchell{at}dundee.ac.uk

  • This work was funded by AstraZeneca and The Wellcome Trust.

  • Abbreviations used are::
    UGT
    uridine diphosphate glucuronosyltransferase
    HLM
    human liver microsomes
    HKM
    human kidney microsomes
    DLM
    dog liver microsomes
    DKM
    dog kidney microsomes
    UDPGA
    UDP glucuronic acid
    CLint
    intrinsic clearance
    • Received April 13, 2000.
    • Accepted October 5, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (2)
Drug Metabolism and Disposition
Vol. 29, Issue 2
1 Feb 2001
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Research ArticleArticle

Evidence for Significant Differences in Microsomal Drug Glucuronidation by Canine and Human Liver and Kidney

Matthew G. Soars, Robert J. Riley, Karen A. B. Findlay, Marcus J. Coffey and Brian Burchell
Drug Metabolism and Disposition February 1, 2001, 29 (2) 121-126;

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Research ArticleArticle

Evidence for Significant Differences in Microsomal Drug Glucuronidation by Canine and Human Liver and Kidney

Matthew G. Soars, Robert J. Riley, Karen A. B. Findlay, Marcus J. Coffey and Brian Burchell
Drug Metabolism and Disposition February 1, 2001, 29 (2) 121-126;
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