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DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS

J. Andrew Williams, Ruth Hyland, Barry C. Jones, Dennis A. Smith, Susan Hurst, Theunis C. Goosen, Vincent Peterkin, Jeffrey R. Koup and Simon E. Ball
Drug Metabolism and Disposition November 2004, 32 (11) 1201-1208; DOI: https://doi.org/10.1124/dmd.104.000794
J. Andrew Williams
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Ruth Hyland
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Barry C. Jones
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Dennis A. Smith
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Susan Hurst
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Theunis C. Goosen
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Vincent Peterkin
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Jeffrey R. Koup
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Abstract

Glucuronidation is a listed clearance mechanism for 1 in 10 of the top 200 prescribed drugs. The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans. Spurred on by interest in developing potent and selective inhibitors for improved confidence around UGT reaction phenotyping, and the increased availability of recombinant forms of human UGTs, several recent studies have reported in vitro inhibition of UGT enzymes. In some cases, the observed potency of UGT inhibitors in vitro has been interpreted as having potential relevance in humans via pharmacokinetic drug-drug interactions. Although there are reported examples of clinically relevant drug-drug interactions for UGT substrates, exposure increases of the aglycone are rarely greater than 100% in the presence of an inhibitor relative to its absence (i.e., AUCi/AUC ≤2). This small magnitude in change is in contrast to drugs primarily cleared by cytochrome P450 enzymes, where exposures have been reported to increase as much as 35-fold on coadministration with an inhibitor (e.g., ketoconazole inhibition of CYP3A4-catalyzed terfenadine metabolism). In this article the evidence for purported clinical relevance of potent in vitro inhibition of UGT enzymes will be assessed, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data on the pharmacokinetic drug-drug interactions of drugs primarily cleared by glucuronidation.

Footnotes

  • Presented as an oral communication by R.H. at the Drug Glucuronidation Workshop in Dundee, Scotland on September 8, 2004.

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

  • doi:10.1124/dmd.104.000794.

  • ABBREVIATIONS: P450, cytochrome P450; AUC, area under the curve (a measure of drug exposure); AUCi/AUC, ratio of drug exposure in the presence of an inhibitor of clearance compared with its absence; AZT, 3′-azido-2′,3′-dideoxythymidine, zidovudine; CI-1027, gemcabene; HMF, 3′,4′,5,5′,6,7-hexamethoxyflavone; I/Ki, ratio of inhibitor concentration to inhibitory constant; UGT, UDP-glucuronosyltransferase.

  • Embedded ImageJ. Andrew Williams is an Associate Research Fellow in the Department of Pharmacokinetics, Dynamics and Metabolism at Pfizer Global Research and Development in Ann Arbor, Michigan. He received a B.Sc. in Genetics from the University of Wales, Swansea in 1989, a Master of Science in Toxicology from the University of Birmingham, England in 1991, and a Ph.D. in Pharmacology (Drug Metabolism) from the University of Aberdeen, Scotland in 1995. Current research interests include pharmacogenomics of drug-metabolizing enzymes and transporters related to drug disposition and pharmacodynamics, ligand interactions with human CYP3A and UGT enzymes, and novel approaches to simulate and/or predict metabolic clearance and metabolic drug-drug interactions.

    • Received June 1, 2004.
    • Accepted August 9, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (11)
Drug Metabolism and Disposition
Vol. 32, Issue 11
1 Nov 2004
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DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS
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OtherMINIREVIEWS

DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS

J. Andrew Williams, Ruth Hyland, Barry C. Jones, Dennis A. Smith, Susan Hurst, Theunis C. Goosen, Vincent Peterkin, Jeffrey R. Koup and Simon E. Ball
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1201-1208; DOI: https://doi.org/10.1124/dmd.104.000794

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DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS

J. Andrew Williams, Ruth Hyland, Barry C. Jones, Dennis A. Smith, Susan Hurst, Theunis C. Goosen, Vincent Peterkin, Jeffrey R. Koup and Simon E. Ball
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1201-1208; DOI: https://doi.org/10.1124/dmd.104.000794
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    • Abstract
    • Clinical Relevance of Cytochrome P450 versus UDP-Glucuronosyltransferase Inhibition in Vitro?
    • Exposure (AUCi/AUC) Ratios >2 for UGT Substrates: Absence of Evidence?
    • Exposure (AUCi/AUC) Ratios >2 for UGT Substrates: Evidence of Absence
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