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Research ArticleMetabolism, Transport, and Pharmacogenomics

In Vitro Inhibition of Human Aldehyde Oxidase Activity by Clinically Relevant Concentrations of Gefitinib and Erlotinib: Comparison with Select Metabolites, Molecular Docking Analysis, and Impact on Hepatic Metabolism of Zaleplon and Methotrexate

Wee Kiat Tan, Alyssa Rui Yi Tan, Punitha Sivanandam, Ernest Jing Hui Goh, Ze Ping Yap, Nur Fazilah Saburulla, Karl Austin-Muttitt, Jonathan G.L. Mullins and Aik Jiang Lau
Journal of Pharmacology and Experimental Therapeutics August 2020, 374 (2) 295-307; DOI: https://doi.org/10.1124/jpet.120.265249
Wee Kiat Tan
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Alyssa Rui Yi Tan
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Punitha Sivanandam
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Ernest Jing Hui Goh
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Ze Ping Yap
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Nur Fazilah Saburulla
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Karl Austin-Muttitt
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Jonathan G.L. Mullins
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Aik Jiang Lau
Department of Pharmacy, Faculty of Science (W.K.T., A.R.Y.T., P.S., E.J.H.G., Z.P.Y., N.F.S., A.J.L.) and Department of Pharmacology, Yong Loo Lin School of Medicine (A.J.L.), National University of Singapore, Singapore, Singapore; and Institute of Life Science, Swansea University Medical School, Swansea, United Kingdom (K.A.-M., J.G.L.M.)
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Abstract

Gefitinib and erlotinib are epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) with activity against metastatic non–small cell lung cancer. Aldehyde oxidase-1 (AOX1) is a cytosolic drug-metabolizing enzyme. We conducted an experimental and molecular docking study on the effect of gefitinib, erlotinib, and select metabolites on the in vitro catalytic activity of AOX1, as assessed by carbazeran 4-oxidation, and determined the impact of AOX1 inhibition on hepatic metabolism of zaleplon and methotrexate. Gefitinib, desmorpholinopropylgefitinib, erlotinib, desmethylerlotinib, and didesmethylerlotinib inhibited human hepatic cytosolic carbazeran 4-oxidation by a competitive mode, with inhibition constants in submicromolar or low micromolar concentrations. Desmethylgefitinib did not affect AOX1 catalytic activity. A similar pattern was obtained when investigated with human kidney cytosol or recombinant AOX1. The differential effect of gefitinib on human, rat, and mouse hepatic AOX1 catalytic activity suggests species-dependent chemical inhibition of AOX1. Erlotinib was considerably more potent than gefitinib in decreasing hepatic cytosolic zaleplon 5-oxidation and methotrexate 7-oxidation. Molecular docking analyses provided structural insights into the interaction between EGFR-TKIs and AOX1, with key residues and bonds identified, which provided favorable comparison and ranking of potential inhibitors. Based on the US Food and Drug Administration guidance to assess the risk of drug-drug interactions, the calculated R1 values indicate that further investigations are warranted to determine whether gefitinib and erlotinib impact AOX1-mediated drug metabolism in vivo. Overall, erlotinib desmethylerlotinib, didesmethylerlotinib, gefitinib, and desmorpholinopropylgefitinib are potent inhibitors of human AOX1 catalytic function and hepatic metabolism of zaleplon and methotrexate, potentially affecting drug efficacy or toxicity.

SIGNIFICANCE STATEMENT As epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib are first-line pharmacotherapy for metastatic non–small cell lung cancer. Our experimental findings indicate that clinically relevant concentrations of gefitinib, desmorpholinopropylgefitinib, erlotinib, desmethylerlotinib, and didesmethylerlotinib, but not desmethylgefitinib, inhibit human aldehyde oxidase (AOX1) catalytic activity and hepatic cytosolic metabolism of zaleplon and methotrexate. Molecular docking analysis provide structural insights into the key AOX1 interactions with these EGFR-TKIs. Our findings may trigger improved strategies for new EGFR-TKI design and development.

Footnotes

    • Received January 19, 2020.
    • Accepted May 1, 2020.
  • This research was supported by the Singapore Ministry of Education Academic Research Fund Tier 1 [Grant R-148-000-218-112 to A.J.L.] and the Singapore Ministry of Health’s National Medical Research Council under its Cooperative Basic Research Grant scheme [Grant R-148-000-225-511 to A.J.L.]. The molecular docking was undertaken using the Supercomputing Wales research facility.

  • https://doi.org/10.1124/jpet.120.265249.

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

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 2
1 Aug 2020
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In Vitro Inhibition of Human Aldehyde Oxidase Activity by Clinically Relevant Concentrations of Gefitinib and Erlotinib: Comparison with Select Metabolites, Molecular Docking Analysis, and Impact on Hepatic Metabolism of Zaleplon and Methotrexate
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Research ArticleMetabolism, Transport, and Pharmacogenomics

AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites

Wee Kiat Tan, Alyssa Rui Yi Tan, Punitha Sivanandam, Ernest Jing Hui Goh, Ze Ping Yap, Nur Fazilah Saburulla, Karl Austin-Muttitt, Jonathan G.L. Mullins and Aik Jiang Lau
Journal of Pharmacology and Experimental Therapeutics August 1, 2020, 374 (2) 295-307; DOI: https://doi.org/10.1124/jpet.120.265249

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Research ArticleMetabolism, Transport, and Pharmacogenomics

AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites

Wee Kiat Tan, Alyssa Rui Yi Tan, Punitha Sivanandam, Ernest Jing Hui Goh, Ze Ping Yap, Nur Fazilah Saburulla, Karl Austin-Muttitt, Jonathan G.L. Mullins and Aik Jiang Lau
Journal of Pharmacology and Experimental Therapeutics August 1, 2020, 374 (2) 295-307; DOI: https://doi.org/10.1124/jpet.120.265249
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