Inactivation of Human Aldehyde Oxidase by Small Sulfhydryl-Containing Reducing Agents

Esmaeeli, Mariam; Nimtz, Manfred; Jänsch, Lothar; Ruddock, L.W.; Leimkühler, Silke

doi:10.1124/dmd.122.001244

Drug Metab Dispos

2023

DOI: 10.1124/dmd.122.001244

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Inactivation of Human Aldehyde Oxidase by Small Sulfhydryl-Containing Reducing Agents

Mariam Esmaeeli

Manfred Nimtz

Lothar Jänsch

et al.

Abstract: Human aldehyde oxidase (hAOX1) is a molybdoflavoenzyme that belongs to the xanthine oxidase (XO) family. hAOX1 is involved in phase I drug metabolism, but its physiological role is not fully understood to date and preclinical studies consistently underestimated hAOX1 clearance. In the present work, we report an unexpected effect of the common sulfhydrylcontaining reducing agents, e.g. dithiothreitol (DTT), on the activity of hAOX1 and mouse

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Challenges and Opportunities for In Vitro–In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance: Toward a Roadmap for Quantitative Translation

Izat,

Bolleddula,

Abbasi

et al. 2023

Drug Metab Dispos

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Underestimation of AO-mediated clearance by current in vitro assays leads to uncertainty in human dose projections, thereby reducing the likelihood of success in drug development. In the present study we first evaluated the current drug development practices for AO substrates. Next, the overall predictive performance of in vitro-in vivo extrapolation (IVIVE) of unbound hepatic intrinsic clearance (CL int,u ) and unbound hepatic intrinsic clearance by AO (CL int,u,AO ) was assessed using a comprehensive literature database of in vitro (human cytosol/ S9/ hepatocytes) and in vivo (iv/oral) data collated for 22 AO substrates (total of 100 datapoints from multiple studies). Correction for unbound fraction in the incubation (fu inc ) was done by experimental data or in silico predictions. The fraction metabolized by AO (fm AO ) determined via in vitro/in vivo approaches was found to be highly variable. The geometric mean fold errors (gmfe) for scaled CL int,u (mL/min/kg) were 10.4 for human hepatocytes, 5.6 for human liver cytosols, and 5.0 for human liver S9, respectively. Application of these gmfe's as empirical scaling factors improved predictions (45-57% within 2-fold of observed) compared with no correction (11-27% within 2-fold), with the scaling factors qualified by leave-oneout cross-validation. A road map for quantitative translation was then proposed following a critical evaluation on the in vitro and clinical methodology to estimate in vivo fm AO . In conclusion, the study provides the most robust system-specific empirical scaling factors to-date as a pragmatic approach for the prediction of in vivo CL int,u,AO in the early stages of drug development.

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Challenges and Opportunities for In Vitro–In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance: Toward a Roadmap for Quantitative Translation

Izat,

Bolleddula,

Abbasi

et al. 2023

Drug Metab Dispos

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Inactivation of Human Aldehyde Oxidase by Small Sulfhydryl-Containing Reducing Agents

Cited by 1 publication

References 39 publications

Challenges and Opportunities for In Vitro–In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance: Toward a Roadmap for Quantitative Translation

Challenges and Opportunities for In Vitro–In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance: Toward a Roadmap for Quantitative Translation

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