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Infigratinib is a Reversible Inhibitor and Mechanism-based Inactivator of Cytochrome P450 3A4

Lloyd Wei Tat Tang, Jian Wei Teng, Siew Kwan Koh, Lei Zhou, Mei Lin Go, Eric Chun Yong Chan, Ravi Kumar Verma and Hao Fan
Drug Metabolism and Disposition July 29, 2021, DMD-AR-2021-000508; DOI: https://doi.org/10.1124/dmd.121.000508
Lloyd Wei Tat Tang
1Pharmacy, National University of Singapore, Singapore
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  • ORCID record for Lloyd Wei Tat Tang
Jian Wei Teng
2National University of Singapore, Singapore
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Siew Kwan Koh
3Singapore Eye Research Institute, Singapore
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Lei Zhou
3Singapore Eye Research Institute, Singapore
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Mei Lin Go
2National University of Singapore, Singapore
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Eric Chun Yong Chan
1Pharmacy, National University of Singapore, Singapore
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  • For correspondence: phaccye@nus.edu.sg
Ravi Kumar Verma
4Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore
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Hao Fan
4Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore
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Abstract

Infigratinib (INF) is a promising selective inhibitor of fibroblast growth factor receptors 1-3 that has recently been accorded both orphan drug designation and priority review status by the U.S Food and Drug Administration for the treatment of advanced cholangiocarcinoma. Its propensity to undergo bioactivation to electrophilic species was recently expounded upon. However, other than causing aberrant idiosyncratic toxicities, these reactive intermediates may elicit mechanism-based inactivation (MBI) of cytochrome P450 enzymes (CYP450). In this study, we investigated the interactions between INF and the most abundant hepatic cytochrome P450 3A4 (CYP3A4). Our findings revealed that apart from being a potent noncompetitive reversible inhibitor of CYP3A4, INF inactivated CYP3A4 in a time-, concentration- and NADPH-dependent manner with KI, kinact and partition ratio of 2.45 µM, 0.053 min-1 and 41 respectively when rivaroxaban was employed as the probe substrate. Co-incubation with testosterone (alternative CYP3A substrate) or ketoconazole (direct CYP3A inhibitor) attenuated the rate of inactivation whereas the inclusion of glutathione and catalase did not confer such protection. The lack of enzyme activity recovery following dialysis for 4 hours and oxidation with potassium ferricyanide, coupled with the absence of the characteristic Soret peak signature collectively substantiated that inactivation of CYP3A4 by INF was not mediated by the formation of quasi-irreversible metabolite-intermediate complexes but rather through irreversible covalent adduction to the prosthetic heme and/or apoprotein. Finally, glutathione trapping and high-resolution mass spectrometry experimental results unravelled two plausible bioactivation mechanisms of INF arising from the generation of a p-benzoquinone diimine and epoxide reactive intermediate.

Significance Statement The potential of infigratinib (INF) to cause mechanism-based inactivation (MBI) of CYP3A4 was unknown. We report the reversible noncompetitive inhibition and irreversible covalent MBI of CYP3A4 by INF and proposed two potential bioactivation pathways implicating p-benzoquinone diimine and epoxide reactive intermediates. Findings from this study lay the groundwork for future investigation of clinically-relevant drug-drug interactions between INF and concomitant substrates of CYP3A4.

  • CYP3A4
  • enzyme inactivation/mechanism-based inhibition
  • reactive metabolites
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (5)
Drug Metabolism and Disposition
Vol. 50, Issue 5
1 May 2021
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Inhibition and Inactivation of CYP3A4 by Infigratinib

Lloyd Wei Tat Tang, Jian Wei Teng, Siew Kwan Koh, Lei Zhou, Mei Lin Go, Eric Chun Yong Chan, Ravi Kumar Verma and Hao Fan
Drug Metabolism and Disposition July 29, 2021, DMD-AR-2021-000508; DOI: https://doi.org/10.1124/dmd.121.000508

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Inhibition and Inactivation of CYP3A4 by Infigratinib

Lloyd Wei Tat Tang, Jian Wei Teng, Siew Kwan Koh, Lei Zhou, Mei Lin Go, Eric Chun Yong Chan, Ravi Kumar Verma and Hao Fan
Drug Metabolism and Disposition July 29, 2021, DMD-AR-2021-000508; DOI: https://doi.org/10.1124/dmd.121.000508
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