Is there enough evidence to classify cycloalkyl amine substituents as structural alerts?

Kalgutkar, Amit S.; Driscoll, James P.

doi:10.1016/j.bcp.2020.113796

Cited by 18 publications

(20 citation statements)

References 85 publications

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“…39 AO-mediated metabolism has been reported as a detoxication pathway of iminium intermediates, converting the reactive species to stable lactams. 41,42 The findings of the present study add to a growing body of literature regarding the role of P450 enzymes in the metabolic activation of tyrosine kinase inhibitors. 43−45 Bioactivation of kinase inhibitors has been associated with time-dependent P450 inhibition and drug-induced liver injury.…”

Section: Chemical Research In Toxicologysupporting

confidence: 57%

“…It should be noted that preincubations were conducted with 25 μM hydralazine, which has been shown to be relatively selective for AO over P450 enzymes . AO-mediated metabolism has been reported as a detoxication pathway of iminium intermediates, converting the reactive species to stable lactams. , …”

Section: Discussionmentioning

confidence: 99%

“…P450 3A4 has been shown to catalyze the bioactivation of several hepatotoxic tyrosine kinase inhibitors, including dasatinib, gefitinib, erlotinib, lapatinib, and sunitinib, leading to the formation of reactive quinoneimine products trapped as glutathione conjugates. ,− Other kinase inhibitors, such as imatinib, masitinib, and avitinib, can form reactive iminium intermediates trapped as cyano adducts. ,, Reactive metabolite formation is proposed as a key initiating event in the development of drug-induced liver injury. , Electrophilic metabolites can bind to cellular thiols and other nucleophilic residues, potentially leading to protein covalent modification, cell stress, immune activation and inflammatory responses, and organ toxicity . A recent report suggests that iminium intermediates may have less toxicity liability compared to other electrophilic metabolites . However, the actual mechanisms involved in masitinib-induced liver injury remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…53 A recent report suggests that iminium intermediates may have less toxicity liability compared to other electrophilic metabolites. 41 However, the actual mechanisms involved in masitinib-induced liver injury remain unclear. Masitinib has also been associated with cardiotoxicity by an unknown mechanism.…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

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Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib

Latham

Oskin

Crouch

et al. 2022

Chem. Res. Toxicol.

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Masitinib is a small molecule tyrosine kinase inhibitor under investigation for the treatment of amyotrophic lateral sclerosis, mastocytosis, and COVID-19. Hepatotoxicity has been reported in some patients while taking masitinib. The liver injury is thought to involve hepatic metabolism of masitinib by cytochrome P450 (P450) enzymes to form chemically reactive, potentially toxic metabolites. The goal of the current investigation was to determine the P450 enzymes involved in the metabolic activation of masitinib in vitro. In initial studies, masitinib (30 μM) was incubated with pooled human liver microsomes in the presence of NADPH and potassium cyanide to trap reactive iminium ion metabolites as cyano adducts. Masitinib metabolites and cyano adducts were analyzed using reversed-phase liquid chromatography–tandem mass spectrometry. The primary active metabolite, N-desmethyl masitinib (M485), and several oxygenated metabolites were detected along with four reactive metabolite cyano adducts (MCN510, MCN524, MCN526, and MCN538). To determine which P450 enzymes were involved in metabolite formation, reaction phenotyping experiments were conducted by incubation of masitinib (2 μM) with a panel of recombinant human P450 enzymes and by incubation of masitinib with human liver microsomes in the presence of P450-selective chemical inhibitors. In addition, enzyme kinetic assays were conducted to determine the relative kinetic parameters (apparent K m and V max) of masitinib metabolism and cyano adduct formation. Integrated analysis of the results from these experiments indicates that masitinib metabolic activation is catalyzed primarily by P450 3A4 and 2C8, with minor contributions from P450 3A5 and 2D6. These findings provide further insight into the pathways involved in the generation of reactive, potentially toxic metabolites of masitinib. Future studies are needed to evaluate the impact of masitinib metabolism on the toxicity of the drug in vivo.

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Section: Chemical Research In Toxicologysupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chemical Research In Toxicologymentioning

confidence: 99%

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Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib

Latham

Oskin

Crouch

et al. 2022

Chem. Res. Toxicol.

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“…As previously reported, alicyclic amines are oxidized by cytochrome P450 and other drug-metabolizing enzymes to iminium ions [ 45 , 46 ]. Furthermore, iminium ions are strong nucleophiles that can be covalently bonded to proteins or deoxyribonucleic acid bases and are known to mediate many toxicities [ 47 , 48 ]. These reactive iminium intermediates may be associated with the reported side effects of donepezil.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Metabolism of Donepezil in Liver Microsomes Using Non-Targeted Metabolomics

et al. 2021

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Donepezil is a reversible acetylcholinesterase inhibitor that is currently the most commonly prescribed drug for the treatment of Alzheimer’s disease. In general, donepezil is known as a safe and well-tolerated drug, and it was not associated with liver abnormalities in several clinical trials. However, rare cases of drug-related liver toxicity have been reported since it has become commercially available. Few studies have investigated the metabolic profile of donepezil, and the mechanism of liver damage caused by donepezil has not been elucidated. In this study, the in vitro metabolism of donepezil was investigated using liquid chromatography–tandem mass spectrometry based on a non-targeted metabolomics approach. To identify metabolites, the data were subjected to multivariate data analysis and molecular networking. A total of 21 donepezil metabolites (17 in human liver microsomes, 21 in mice liver microsomes, and 17 in rat liver microsomes) were detected including 14 newly identified metabolites. One potential reactive metabolite was identified in rat liver microsomal incubation samples. Metabolites were formed through four major metabolic pathways: (1) O-demethylation, (2) hydroxylation, (3) N-oxidation, and (4) N-debenzylation. This study indicates that a non-targeted metabolomics approach combined with molecular networking is a reliable tool to identify and detect unknown drug metabolites.

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In Silico Toxicology

Bassan,

Beilke,

Cross

et al. 2023

Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

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Is there enough evidence to classify cycloalkyl amine substituents as structural alerts?

Cited by 18 publications

References 85 publications

Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib

Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib

In Vitro Metabolism of Donepezil in Liver Microsomes Using Non-Targeted Metabolomics

In Silico Toxicology

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