Toxicological potential of acyl glucuronides and its assessment

Iwamura, Atsushi; Nakajima, Miki; Oda, Shingo; Yokoi, Tsuyoshi

doi:10.1016/j.dmpk.2016.11.002

Cited by 47 publications

(44 citation statements)

References 108 publications

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“…UGT inhibition mechanisms have not been fully unraveled and RM involvement has never been suggested as a causative factor of TKI UGT1A1 inhibition. However, acyl glucuronides, through transacylation and glycation mechanisms, could potentially lead to TDI and toxicity as reported for several drugs bearing a carboxylic acid moiety . Thus, it is not unlikely that TKI metabolized to carboxylic acid derivatives could generate acyl glucuronides involved in their hepatotoxicity, but to the best of our knowledge, it has not been reported yet.…”

Section: Inhibition Of Udp‐glucuronosyltransferases By Tkimentioning

confidence: 83%

“…However, acyl glucuronides, through transacylation and glycation mechanisms, could potentially lead to TDI and toxicity as reported for several drugs bearing a carboxylic acid moiety. [150][151][152] Even though their underlying mechanisms are not fully elucidated, the involvement of RM resulting from the metabolic activation of structural alerts has been suspected. A chemical approach to preventing toxicities/DDI might be to avoid structural alerts to reduce RM formation but this strategy may also induce drug attrition in the early stage of drug development.…”

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confidence: 99%

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Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Paludetto

Puisset

Chatelut

et al. 2019

Medicinal Research Reviews

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Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI are associated with toxicities including liver injury that may be serious and even life‐threatening. Many of them require warnings in drug labeling against liver injury, and five of them have Black Box Warning (BBW) labels. Although drug‐induced liver injury is a matter of clinical and industrial concern, little is known about the underlying mechanisms that likely involve reactive metabolites (RM). RM are electrophiles or radicals originating from the metabolic activation of particular functional groups, known as structural alerts or toxicophores. RM are able to covalently bind to proteins and macromolecules, causing cellular damage and even cell death. If the adducted protein is the enzyme involved in RM formation, time‐dependent inhibition of the enzyme—also called mechanism‐based inhibition (MBI) or inactivation—can occur and lead to pharmacokinetic drug‐drug interactions. To mitigate RM liabilities, common practice in drug development includes avoiding structural alerts and assessing RM formation via RM trapping screens with soft and hard nucleophiles (glutathione, potassium cyanide, and methoxylamine) in liver microsomes. RM‐positive derivatives are further optimized to afford drug candidates with blocked or minimized bioactivation potential. However, different structural alerts are still commonly used scaffolds in drug design, including in TKI structures. This review focuses on the current state of knowledge of the relations among TKI structures, bioactivation pathways, RM characterization, and hepatotoxicity and cytochrome P450 MBI in vitro.

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Section: Inhibition Of Udp‐glucuronosyltransferases By Tkimentioning

confidence: 83%

mentioning

confidence: 99%

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Paludetto

Puisset

Chatelut

et al. 2019

Medicinal Research Reviews

View full text Add to dashboard Cite

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“…The acylglucuronide can be converted into fasiglifam‐ S ‐acyl‐GSH (M2); the latter biotransformation is NADPH‐dependent, suggesting the reactivity and instability of acylglucuronide. It has been reported that some acylglucuronides can form 2‐ O ‐acylglucuronide, 3‐ O ‐acylglucuronide and 4‐ O ‐acylglucuronide via intramolecular rearrangement and these isomers can react with –NH 2 of protein to form a Schiff base and thus leading to toxicity . Therefore, this metabolic pathway may be the perpetrator of its hepatotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…Drugs with no significant hepatic metabolism rarely cause hepatotoxicity, while an increased risk was found for drugs with >50% hepatic metabolism . There are several examples of carboxylic acid‐containing drugs being withdrawn from the market or receiving warning, such as diclofenac, zomepirac, ibufenac and benoxaprofen . The predominant reason for their withdrawal is the formation of reactive metabolites, including acylglucuronide, which can cause severe hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 There are several examples of carboxylic acid-containing drugs being withdrawn from the market or receiving warning, such as diclofenac, zomepirac, ibufenac and benoxaprofen. 13 The predominant reason for their withdrawal is the formation of reactive metabolites, including acylglucuronide, which can cause severe hepatotoxicity. Although a recent publication indicated that fasiglifam-acylglucuronide could be involved in its hepatotoxicity, 7 the detailed metabolic profiles of fasiglifam remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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In vitro and in vivo metabolic profiles of fasiglifam using ultrahigh‐performance liquid chromatography combined with Q‐Exactive Orbitrap tandem mass spectrometry

Wang

et al. 2018

Rapid Comm Mass Spectrometry

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Principles of Drug Metabolism

Dalvie

Testa

2021

Burger's Medicinal Chemistry and Drug Discovery

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Metabolism is a complex process that involves enzymatic modification of drugs and xenobiotics and is one of the most important determinants of their fate in the body. Although the drug metabolism is considered a process of detoxification, the products of metabolism can play an important role in the pharmacology and toxicology of the parent drug. Studying the metabolism of newly synthesized molecules is a valuable strategy that allows one to identify the underlying problems, such as “soft spots,” or metabolic activation, that affect the systemic exposure of a molecule and safety and efficacy. Early investigative metabolism of new compounds has helped in assessing the bioactivation potential of these candidates and thus, avoid reactive metabolites or put mitigation strategies in place. Metabolism can also lead to pharmacologically active metabolites. These metabolites can have superior pharmacological, pharmacokinetic, and safety profiles compared to their parent drug and can therefore be developed as drugs. This chapter provides an overview of the enzymes involved in the metabolism of xenobiotics and the different metabolic pathways. An attempt has been made to illustrate these principles with pertinent example with a brief review of topics of potential interests to aspiring medicinal chemists namely, the factors that may influence biotransformation or applications to predict the sites of metabolism. While the medicinal chemists are not expected to possess a deep knowledge of the mechanistic aspects, the hope is that the principles outlined in this chapter will assist them in designing a better drug.

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Toxicological potential of acyl glucuronides and its assessment

Cited by 47 publications

References 108 publications

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

In vitro and in vivo metabolic profiles of fasiglifam using ultrahigh‐performance liquid chromatography combined with Q‐Exactive Orbitrap tandem mass spectrometry

Principles of Drug Metabolism

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