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Research ArticleMinireview

Low-Turnover Drug Molecules: A Current Challenge for Drug Metabolism Scientists

J. Matthew Hutzler, Barbara J. Ring and Shelby R. Anderson
Drug Metabolism and Disposition December 2015, 43 (12) 1917-1928; DOI: https://doi.org/10.1124/dmd.115.066431
J. Matthew Hutzler
Q2 Solutions, a Quintiles Quest Joint Venture, Bioanalytical and ADME Laboratories, Indianapolis, Indiana
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Barbara J. Ring
Q2 Solutions, a Quintiles Quest Joint Venture, Bioanalytical and ADME Laboratories, Indianapolis, Indiana
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Shelby R. Anderson
Q2 Solutions, a Quintiles Quest Joint Venture, Bioanalytical and ADME Laboratories, Indianapolis, Indiana
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Abstract

In vitro assays using liver subcellular fractions or suspended hepatocytes for characterizing the metabolism of drug candidates play an integral role in the optimization strategy employed by medicinal chemists. However, conventional in vitro assays have limitations in their ability to predict clearance and generate metabolites for low-turnover (slowly metabolized) drug molecules. Due to a rapid loss in the activity of the drug-metabolizing enzymes, in vitro incubations are typically performed for a maximum of 1 hour with liver microsomes to 4 hours with suspended hepatocytes. Such incubations are insufficient to generate a robust metabolic response for compounds that are slowly metabolized. Thus, the challenge of accurately estimating low human clearance with confidence has emerged to be among the top challenges that drug metabolism scientists are confronted with today. In response, investigators have evaluated novel methodologies to extend incubation times and more sufficiently measure metabolism of low-turnover drugs. These methods include plated human hepatocytes in monoculture, and a novel in vitro methodology using a relay of sequential incubations with suspended cryopreserved hepatocytes. In addition, more complex in vitro cellular models, such as HepatoPac (Hepregen, Medford, MA), a micropatterned hepatocyte-fibroblast coculture system, and the HµREL (Beverley Hills, CA) hepatic coculture system, have been developed and characterized that demonstrate prolonged enzyme activity. In this review, the advantages and disadvantages of each of these in vitro methodologies as it relates to the prediction of clearance and metabolite identification will be described in an effort to provide drug metabolism scientists with the most up-to-date experimental options for dealing with the complex issue of low-turnover drug candidates.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (12)
Drug Metabolism and Disposition
Vol. 43, Issue 12
1 Dec 2015
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Research ArticleMinireview

The Challenge of Low-Turnover Drug Molecules

J. Matthew Hutzler, Barbara J. Ring and Shelby R. Anderson
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1917-1928; DOI: https://doi.org/10.1124/dmd.115.066431

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Research ArticleMinireview

The Challenge of Low-Turnover Drug Molecules

J. Matthew Hutzler, Barbara J. Ring and Shelby R. Anderson
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1917-1928; DOI: https://doi.org/10.1124/dmd.115.066431
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