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Research ArticleArticle

Contribution of UGT Enzymes to Human Drug Metabolism Stereoselectivity: A Case Study of Medetomidine, RO5263397, Propranolol, and Testosterone

Nicolò Milani, NaHong Qiu and Stephen Fowler
Drug Metabolism and Disposition March 2023, 51 (3) 306-317; DOI: https://doi.org/10.1124/dmd.122.001024
Nicolò Milani
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, Basel, Switzerland (N.M., N.Q., S.F.) and Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy (N.M.)
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NaHong Qiu
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, Basel, Switzerland (N.M., N.Q., S.F.) and Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy (N.M.)
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Stephen Fowler
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel, Basel, Switzerland (N.M., N.Q., S.F.) and Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy (N.M.)
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Abstract

The enantiomeric forms of chiral compounds have identical physical properties but may vary greatly in their metabolism by individual enzymes. Enantioselectivity in UDP-glucuronosyl transferase (UGT) metabolism has been reported for a number of compounds and with different UGT isoforms involved. However, the impact of such individual enzyme results on overall clearance stereoselectivity is often not clear. The enantiomers of medetomidine, RO5263397, and propranolol and the epimers testosterone and epitestosterone exhibit more than a 10-fold difference in glucuronidation rates by individual UGT enzymes. In this study, we examined the translation of human UGT stereoselectivity to hepatic drug clearance considering the combination of multiple UGTs to overall glucuronidation, the contribution of other metabolic enzymes such as cytochrome P450s (P450s), and the potential for differences in protein binding and blood/plasma partitioning. For medetomidine and RO5263397, the high individual enzyme (UGT2B10) enantioselectivity translated into ∼3- to >10-fold differences in predicted human hepatic in vivo clearance. For propranolol, the UGT enantioselectivity was irrelevant in the context of high P450 metabolism. For testosterone, a complex picture emerged due to differential epimeric selectivity of various contributing enzymes and potential for extrahepatic metabolism. Quite different patterns of P450- and UGT-mediated metabolism were observed across species, as well as differences in stereoselectivity, indicating that extrapolation from human enzyme and tissue data are essential when predicting human clearance enantioselectivity.

SIGNIFICANCE STATEMENT Individual enzyme stereoselectivity illustrates the importance of three-dimensional drug-metabolizing enzyme-substrate interactions and is essential when considering the clearance of racemic drugs. However, translation from in vitro to in vivo can be challenging as contributions from multiple enzymes and enzyme classes must be combined with protein binding and blood/plasma partitioning data to estimate the net intrinsic clearance for each enantiomer. Preclinical species may be misleading as enzyme involvement and metabolism stereoselectivity can differ substantially.

Footnotes

    • Received July 8, 2022.
    • Accepted December 1, 2022.
  • This work was funded by F. Hoffmann - La Roche Ltd, Basel, Switzerland.

  • The authors have no conflicts of interest to declare.

  • dx.doi.org/10.1124/dmd.122.001024.

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

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (3)
Drug Metabolism and Disposition
Vol. 51, Issue 3
1 Mar 2023
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Research ArticleArticle

Impact of UGT Stereoselectivity on Drug Clearance

Nicolò Milani, NaHong Qiu and Stephen Fowler
Drug Metabolism and Disposition March 1, 2023, 51 (3) 306-317; DOI: https://doi.org/10.1124/dmd.122.001024

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Research ArticleArticle

Impact of UGT Stereoselectivity on Drug Clearance

Nicolò Milani, NaHong Qiu and Stephen Fowler
Drug Metabolism and Disposition March 1, 2023, 51 (3) 306-317; DOI: https://doi.org/10.1124/dmd.122.001024
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