In vitro oxidation of aldehyde oxidase from rabbit liver: Specificity toward endogenous substrates

Salhen, Khaled S. Al

doi:10.1016/j.jksus.2013.09.002

Cited by 3 publications

(1 citation statement)

References 45 publications

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“…Retinal and pyridoxal are examples of endogenous aldehydes oxidized by AO (Figure 6A). 116,117 Study of vanillin, isovanillin, and protocatechuic aldehyde oxidations found that vanillin was rapidly oxidized by AO (in guinea pig liver), whereas isovanillin was mainly oxidized by ALDH and protocatechuic aldehyde was oxidized by all three tested enzymes (AO, ALDH, and XO) (Figure 6B). 118,119 Further studies with a set of 11 benzaldehydes confirmed that AO plays an important role in the metabolism of aromatic aldehydes.…”

Section: Substrate Specificity and Reactions Catalyzedmentioning

confidence: 99%

Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery

et al. 2019

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Aldehyde oxidase (AO) catalyzes oxidations of azaheterocycles and aldehydes, amide hydrolysis, and diverse reductions. AO substrates are rare among marketed drugs, and many candidates failed due to poor pharmacokinetics, interspecies differences, and adverse effects. As most issues arise from complex and poorly understood AO biology, an effective solution is to stop or decrease AO metabolism. This perspective focuses on rational drug design approaches to modulate AO‑mediated metabolism in drug discovery. AO biological aspects are also covered, as they are complementary to chemical design and important when selecting the experimental system for risk assessment. The authors’ recommendation is an early consideration of AO-mediated metabolism supported by computational and in vitro experimental methods but not an automatic avoidance of AO structural flags, many of which are versatile and valuable building blocks. Preferably, consideration of AO‑mediated metabolism should be part of the multiparametric drug optimization process, with the goal to improve overall drug-like properties.

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Section: Substrate Specificity and Reactions Catalyzedmentioning

confidence: 99%

Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery

et al. 2019

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Aldehyde oxidase; new approaches to old problems

Beedham

2019

Xenobiotica

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A Laboratory-Specific Scaling Factor to Predict the In Vivo Human Clearance of Aldehyde Oxidase Substrates

et al. 2020

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Aldehyde oxidase (AO) efficiently metabolizes a range of compounds with N-containing heterocyclic aromatic rings and/or aldehydes. The limited knowledge of AO activity and abundance (in vitro and in vivo) has led to poor prediction of in vivo systemic clearance (CL) using in vitro-to-in vivo extrapolation (IVIVE) approaches, which for drugs in development can lead to their discontinuation. We aimed to identify appropriate scaling factors (SF) to predict AO CL of future New Chemical Entities (NCE). The metabolism of six AO substrates was measured in human liver cytosol (HLC) and S9 fractions. Measured blood-to-plasma ratios and free fractions (in the in vitro system and in plasma) were used to develop physiologically-based pharmacokinetic (PBPK) models for each compound. The impact of extrahepatic metabolism was explored, and the intrinsic clearance required to recover in vivo profiles was estimated and compared to in vitro measurements. Using HLC data and assuming only hepatic metabolism, a systematic underprediction of clearance was observed (average fold under-prediction was 3.8). Adding extrahepatic metabolism improved the accuracy of the results (average fold error of 1.9). A workflow for predicting metabolism of an NCE by AO is proposed, an empirical (lab-specific) SF of 3 on the predicted CL IV allows a reasonable prediction of the available clinical data. Alternatively, considering also extrahepatic metabolism, a SF of 6.5 applied on the intrinsic clearance (CL int,AO) could be used. Future research should focus on the impact of the in vitro study designs and the contribution of extrahepatic metabolism to AO-mediated clearance to understand the mechanisms behind the systematic under-prediction. Significance Statement This works describes the development of scaling factors to allow in vitro-in vivo extrapolation of the clearance of compounds by aldehyde oxidase metabolism in humans. In addition, PBPK models were developed for each of the AO substrate compounds investigated.

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In vitro oxidation of aldehyde oxidase from rabbit liver: Specificity toward endogenous substrates

Cited by 3 publications

References 45 publications

Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery

Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery

Aldehyde oxidase; new approaches to old problems

A Laboratory-Specific Scaling Factor to Predict the In Vivo Human Clearance of Aldehyde Oxidase Substrates

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