Aldehyde oxidase and its role as a drug metabolizing enzyme

Dalvie, Deepak; Di, Li

doi:10.1016/j.pharmthera.2019.05.011

Cited by 62 publications

(61 citation statements)

References 324 publications

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“…however, the M1 peak on HPLC was not detectable in either sex (data not shown). This is consistent with the previous reports demonstrating that aldehyde oxidase is limited or absent in the liver of dogs (Dalvie & Di, 2019;Garattini & Terao, 2012;Sanoh et al, 2015). Regarding V max values, the variations were approximately 60-to 90fold among species (males: monkeys > mice > humans > rats; females: monkeys > humans > mice > rats).…”

Section: Discussionsupporting

confidence: 92%

Favipiravir biotransformation in liver cytosol: Species and sex differences in humans, monkeys, rats, and mice

Hanioka

Saito

Isobe

et al. 2021

Biopharm & Drug Disp

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Favipiravir is an antiviral agent effective against several RNA viruses that is converted into an inactive oxidative metabolite (M1), mainly by aldehyde oxidase, in humans. In the present study, the biotransformation of favipiravir into M1 in male and female humans, monkeys, rats, and mice was examined in an in vitro system using liver cytosolic fractions. The kinetics for M1 formation followed the Michaelis-Menten model in all species. The K m , V max , and CL int values in humans were 602 µM, 466 pmol/min/mg protein, and 776 nl/min/mg protein in males, respectively, and 713 µM, 404 pmol/min/mg protein, and 567 nl/min/mg protein in females, respectively. Species differences in CL int values were monkeys > humans > mice > rats in both males and females, and the variations for males and females were 120-and 96-fold, respectively. Sex differences in CL int values were males > females in humans and mice, females > males in monkeys and rats, and marked variation (4.3-fold) was noted in mice. This suggests that the roles of aldehyde oxidase in the hepatic metabolism of favipiravir differ extensively depending on the species and sex, and this study will aid in the assessment of the antiviral activities of favipiravir against novel and/or variant viruses.

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Section: Discussionsupporting

confidence: 92%

Favipiravir biotransformation in liver cytosol: Species and sex differences in humans, monkeys, rats, and mice

Hanioka

Saito

Isobe

et al. 2021

Biopharm & Drug Disp

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“…24 Cimetidine coadministration results in a marked inhibition on AO catalyzed oxozaleplon formation and a warning is included in the zaleplon label. 25 Potential DDIs between these drugs and favipiravir should be carefully monitored. Several drugs, such as citalopram, 26 zaleplon, 27 famciclovir, 28 and sulindac, 29 are also metabolized by AO.…”

Section: Regarding Potential Drug-drug Interaction In Pharmacokineticsmentioning

confidence: 99%

Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019‐nCoV Infection

Chen

2020

Clin Pharma and Therapeutics

353

292

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such as interferon-ɑ, lopinavir/ ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA-dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the pharmacokinetic characteristics of favipiravir and possible drug-drug interactions from the view of drug metabolism. We hope this will be helpful for the design of clinical trials for favipiravir in COVID-2019, as data regarding in vitro virus inhibition and efficacy in preclinical animal studies are still not available.[Correction added on 30 April 2020, after first online publication: The first sentence in Abstract has been changed to 'An outbreak of 2019-nCoV infection has spread across the world'].

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“…The rate of metabolite formation from the probe substrate is quantitatively determined. For other membrane bound non‐CYP enzymes, HLM or human liver S9 may be used in inhibition studies, e.g., carboxylesterases (CESs) (Di, ; Di, ), whereas human liver cytosol or S9 are used for studying soluble enzymes, e.g., aldehyde oxidase (AO) (Dalvie & Di, ; Di, ; Zientek, Jiang, Youdim, & Obach, ).…”

Section: Mechanisms On How Perpetrators Alter Pharmacokinetics Of Vicmentioning

confidence: 99%

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Lu¹,

2020

Biopharm & Drug Disp

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Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs are major safety concerns in the clinic. Several drugs have been withdrawn from the market due to perpetrator or victim DDIs. Strategies have been developed to assess DDI risks early in drug discovery to reduce DDI liabilities. High-to-medium throughput assays are available to identify undesirable scaffolds and to guide structural modifications to minimize DDIs. Definitive methods are used at later stages of drug discovery and development to provide a more accurate measurement of DDI parameters and to enable clinical translations. Physiologically based pharmacokinetic modeling and simulations are powerful tools to accurately predict DDIs and to assess risks in the clinic. Although significant advances have been made over the years, many challenges remain for clinical DDI translations. This includes DDIs involving non-cytochrome P450 enzymes, transporters, enzyme-transporter interplay, indirect effects from biologics, and pharmacodynamic based DDI. This review focuses on methods that are used to assess hepatic DDIs caused by enzyme inhibition and induction.

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Aldehyde oxidase and its role as a drug metabolizing enzyme

Cited by 62 publications

References 324 publications

Favipiravir biotransformation in liver cytosol: Species and sex differences in humans, monkeys, rats, and mice

Favipiravir biotransformation in liver cytosol: Species and sex differences in humans, monkeys, rats, and mice

Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019‐nCoV Infection

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

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