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Enzyme Kinetics, Pharmacokinetics, and Inhibition of Aldehyde Oxidase

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Enzyme Kinetics in Drug Metabolism

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2342))

Abstract

Aldehyde oxidase (AO) has emerged as an important drug metabolizing enzyme over the last decade. Several compounds have failed in the clinic because the clearance or toxicity was underestimated by preclinical species. Human AO is much more active than rodent AO, and dogs do not have functional AO. Metabolic products from AO-catalyzed oxidation are generally nonreactive and often they have much lower solubility. AO metabolism is not limited to oxidation as AO can also catalyze reduction of oxygen and nitrite. Reduction of oxygen leads to the reactive oxygen species (ROS) superoxide radical anion and hydrogen peroxide. Reduction of nitrite leads to the formation of nitric oxide with potential pharmacological implications. AO is also reported to catalyze the reductive metabolism of nitro-compounds, N-oxides, sulfoxides, isoxazoles, isothiazoles, nitrite, and hydroxamic acids. These reductive transformations may cause toxicity due to the formation of reactive metabolites. Moreover, the inhibition kinetics are complex, and multiple probe substrates should be used when assessing the potential for DDIs. Finally, AO appears to be amenable to computational predictions of both regioselectivity and rates of reaction, which holds promise for virtual screening.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA

    Erickson M. Paragas

  2. Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck, Boston, MA, USA

    Kanika Choughule

  3. Department of Chemistry, Washington State University, Pullman, WA, USA

    Jeffrey P. Jones

  4. Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck, South San Francisco, CA, USA

    John T. Barr

Authors
  1. Erickson M. Paragas
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  2. Kanika Choughule
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  3. Jeffrey P. Jones
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  4. John T. Barr
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Corresponding author

Correspondence to John T. Barr .

Editor information

Editors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA

    Swati Nagar

  2. Translational Medicine, Novartis Institutes for Biomedical Research, Inc., Cambridge, MA, USA

    Upendra A. Argikar

  3. Independent, Harleysville, PA, USA

    Donald Tweedie

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Paragas, E.M., Choughule, K., Jones, J.P., Barr, J.T. (2021). Enzyme Kinetics, Pharmacokinetics, and Inhibition of Aldehyde Oxidase. In: Nagar, S., Argikar, U.A., Tweedie, D. (eds) Enzyme Kinetics in Drug Metabolism. Methods in Molecular Biology, vol 2342. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1554-6_10

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  • DOI: https://doi.org/10.1007/978-1-0716-1554-6_10

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