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Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance

The AAPS Journal volume 18, pages 1391–1405 (2016)Cite this article

Abstract

Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High-throughput metabolic stability screening has enabled the advancement of compounds with little to no oxidative metabolism. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for non-CYP-mediated metabolism. UGTs, esterases, and aldehyde oxidase are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such pathways including elucidation of major metabolites. To predict human PK parameters for P450-mediated metabolism, in vitro-in vivo extrapolation using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, such methods have not been sufficiently evaluated for non-P450 enzymes. In addition to the involvement of the liver, extrahepatic enzymes (intestine, kidney, lung) are also likely to contribute to these pathways. While there has been considerable progress in predicting metabolic pathways and clearance primarily mediated by the liver, progress in characterizing extrahepatic metabolism and prediction of clearance has been slow. Well-characterized in vitro systems or in vivo animal models to assess drug-drug interaction potential and intersubject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non-CYP-mediated metabolism and to understand the enzymes involved followed by pharmacokinetic studies in the appropriately characterized surrogate species. The review will highlight progress made in establishing in vitro-in vivo correlation, predicting human clearance and avoiding costly clinical failures when non-CYP-mediated metabolic pathways are predominant.

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Acknowledgments

Sincere thanks to Jennifer L. (Bushee) Dumouchel, Mithat Gunduz, Amanda Cirello, and Bindi Sohal for critical discussions. Work in the Potter lab is supported in part by NIH grants CA108775 and AT007531, a Cancer Center Core grant CA21765, and the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital (SJCRH).

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Authors and Affiliations

  1. Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts, USA

    Upendra A. Argikar

  2. Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

    Philip M. Potter

  3. Q2 Solutions, Bioanalytical and ADME Labs, Indianapolis, Indiana, USA

    J. Matthew Hutzler

  4. Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Punit H. Marathe

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  1. Upendra A. Argikar
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  2. Philip M. Potter
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Correspondence to Punit H. Marathe.

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Argikar, U.A., Potter, P.M., Hutzler, J.M. et al. Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance. AAPS J 18, 1391–1405 (2016). https://doi.org/10.1208/s12248-016-9962-6

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KEY WORDS

  • aldehyde oxidase
  • carboxylesterase
  • clearance prediction
  • metabolism
  • reaction phenotyping
  • uridine diphosphoglucuronosyl transferase