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Research ArticleArticle

A New Rapid In Vitro Assay for Assessing Reactivity of Acyl Glucuronides

Sheng Zhong, Russell Jones, Wenzhe Lu, Simone Schadt and Giorgio Ottaviani
Drug Metabolism and Disposition November 2015, 43 (11) 1711-1717; DOI: https://doi.org/10.1124/dmd.115.066159
Sheng Zhong
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China (S.Z., W.L., G.O.) and Roche Innovation Center Basel, Basel, Switzerland (R.J., S.S.)
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Russell Jones
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China (S.Z., W.L., G.O.) and Roche Innovation Center Basel, Basel, Switzerland (R.J., S.S.)
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Wenzhe Lu
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China (S.Z., W.L., G.O.) and Roche Innovation Center Basel, Basel, Switzerland (R.J., S.S.)
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Simone Schadt
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China (S.Z., W.L., G.O.) and Roche Innovation Center Basel, Basel, Switzerland (R.J., S.S.)
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Giorgio Ottaviani
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China (S.Z., W.L., G.O.) and Roche Innovation Center Basel, Basel, Switzerland (R.J., S.S.)
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Abstract

Idiosyncratic drug toxicity is a major challenge for the pharmaceutical industry since complex and multifactorial steps are involved, the dose-dependency is unclear, and its occurrence is not reliably predictable. Whereas the exact mechanisms leading to idiosyncratic toxicity remain elusive in many cases, there are often hints at the involvement of reactive metabolites, such as acyl glucuronides formed by conjugation of carboxylic acids with glucuronic acid. Because the patient-related susceptibilities leading to idiosyncratic toxicity are not sufficiently understood, the best option for the pharmaceutical industry is to minimize drug-related risk factors such as potential acyl glucuronide formation. Here, we describe a rapid in vitro assay for the assessment of the reactivity of acyl glucuronides, on the basis of acyl glucuronide migration, that can support the selection of low-risk drug candidates in the drug discovery phase. Twenty marketed compounds with a wide range of half-lives were tested, their acyl glucuronide migration rates were determined and compared with the half-lives of the respective acyl glucuronides. Ranking of acyl glucuronide stability using this method compared well with the results from existing methodologies. With this method, migration rates >20% would indicate higher risk of reactivity. This simpler approach using the acyl glucuronide migration rate is not dependent on authentic standards, therefore eliminating the requirement for either lengthy chemical synthesis or in vitro biosynthesis and purification of the 1-O-β-glucuronide. This methodology provides a rapid in vitro assay to assess acyl glucuronide stability and reactivity that is well suited for use early in the drug discovery phase.

Footnotes

    • Received July 2, 2015.
    • Accepted August 12, 2015.
  • dx.doi.org/10.1124/dmd.115.066159.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

Assessment of Acyl Glucuronide Reactivity

Sheng Zhong, Russell Jones, Wenzhe Lu, Simone Schadt and Giorgio Ottaviani
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1711-1717; DOI: https://doi.org/10.1124/dmd.115.066159

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Research ArticleArticle

Assessment of Acyl Glucuronide Reactivity

Sheng Zhong, Russell Jones, Wenzhe Lu, Simone Schadt and Giorgio Ottaviani
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1711-1717; DOI: https://doi.org/10.1124/dmd.115.066159
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