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Rapid CommunicationShort Communication

Spironolactone and Canrenone Inhibit UGT2B7-Catalyzed Human Liver and Kidney Microsomal Aldosterone 18β-Glucuronidation: A Potential Drug Interaction

Kathleen M. Knights, Kushari Bowalgaha and John O. Miners
Drug Metabolism and Disposition July 2010, 38 (7) 1011-1014; DOI: https://doi.org/10.1124/dmd.110.032870
Kathleen M. Knights
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Kushari Bowalgaha
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John O. Miners
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Abstract

Elevated plasma concentrations of aldosterone (ALDO) are observed in patients treated with spironolactone. Because ALDO is eliminated via UGT2B7-catalyzed 18β-glucuronidation, this study aimed to determine whether spironolactone and its primary metabolites, canrenone and canrenoic acid, inhibit ALDO 18β-glucuronidation by recombinant UGT2B7 and by human liver (HLM) and human kidney cortical (HKCM) microsomes. Initial experiments characterized the effects of all three compounds on 4-methylumbelliferone and ALDO glucuronidation by recombinant human UGT2B7. IC50 values for spironolactone and canrenone ranged from 26 to 50 μM, whereas canrenoic acid was a weak inhibitor. Inhibitor constant (Ki) values for spironolactone and canrenone inhibition of ALDO 18β-glucuronidation were subsequently determined with HLM, HKCM, and UGT2B7 as the enzyme sources. Spironolactone and canrenone were competitive inhibitors of ALDO 18β-glucuronidation by HLM, HKCM, and UGT2B7. Mean (±) Ki values for spironolactone were 52 ± 22 (HLM) and 34 ± 4 μM (HKCM), and mean (±) Ki values for canrenone were 41 ± 19 (HLM) and 23 ± 2 μM (HKCM). Ki values for spironolactone and canrenone inhibition of ALDO 18β-glucuronidation by recombinant UGT2B7 were 23 and 11 μM, respectively. “Actual” Ki values for spironolactone and canrenone inhibition of ALDO 18β-glucuronidation, which take into account the role of endogenous microsomal inhibitors, are predicted to be 3 to 5 and 2 to 4 μM, respectively. The data indicate that the elevated ALDO concentrations observed in patients treated with spironolactone may be due, at least in part, to a pharmacokinetic interaction, and spironolactone and canrenone should be considered to be potential inhibitors of the UGT2B7-mediated metabolic clearance of drugs in both liver and kidney.

Footnotes

  • The work was funded by the National Health and Medical Research Council of Australia.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032870.

  • ABBREVIATIONS:

    ALDO
    aldosterone
    ALDO 18β-G
    ALDO 18β-glucuronide
    HKCM
    human kidney cortical microsomes
    HLM
    human liver microsomes
    UGT
    UDP-glucuronosyltransferase
    4-MU
    4-methylumbelliferone
    4-MUG
    4-methylumbelliferone-β-d-glucuronide
    UDPGA
    UDP-glucuronic acid
    HEK
    human embryonic kidney.

  • Received February 17, 2010.
  • Accepted March 19, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Rapid CommunicationShort Communication

Spironolactone and Canrenone Inhibit UGT2B7-Catalyzed Human Liver and Kidney Microsomal Aldosterone 18β-Glucuronidation: A Potential Drug Interaction

Kathleen M. Knights, Kushari Bowalgaha and John O. Miners
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1011-1014; DOI: https://doi.org/10.1124/dmd.110.032870

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Rapid CommunicationShort Communication

Spironolactone and Canrenone Inhibit UGT2B7-Catalyzed Human Liver and Kidney Microsomal Aldosterone 18β-Glucuronidation: A Potential Drug Interaction

Kathleen M. Knights, Kushari Bowalgaha and John O. Miners
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1011-1014; DOI: https://doi.org/10.1124/dmd.110.032870
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