LC–MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: In vivo and in vitro metabolic investigation

Attwa, Mohamed W.; Kadi, Adnan A.; AlRabiah, Haitham; Darwish, Hany W.

doi:10.1016/j.jpba.2018.07.032

Cited by 38 publications

(29 citation statements)

References 23 publications

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“…Iminium carbonyl intermediates were also observed after subsequent piperazine oxidation. Similar metabolic activation pathways on the piperazine ring were reported for imatinib 26 in HLM and for entrectinib 10 , masitinib 76 , and ponatinib 68 in RLM (Figure ).…”

Section: Tki Metabolic Activation: Evidence Of Rm Formationsupporting

confidence: 77%

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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: Tki Metabolic Activation: Evidence Of Rm Formationsupporting

confidence: 77%

“…Entrectinib 10 indazole moiety has been reported to be bioactivated to a p ‐quinone‐methide RM 12 since GSH adducts have been detected in vitro in rat liver microsomes. The initial step of the metabolic activation is an aromatic hydroxylation ( 11 ) on the indazole ring (Figure ).…”

Section: Tki Metabolic Activation: Evidence Of Rm Formationmentioning

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

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“…This method lacked applicability for pharmacokinetics studies of entrectinib in humans, and also required a greater sample volume and injection volume, and low sensitivity (Attwa, Darwish, et al, ). Another study lacked the details of the establishment of the method (Attwa, Kadi, et al, ). Therefore, our paper reports the complete development and validation of a simple and sensitive UPLC–MS/MS method to quantify entrectinib in biological samples, and its application to in vivo sample analysis to determine the pharmacokinetic properties of entrectinib in rats.…”

Section: Discussionmentioning

confidence: 99%

“…To the best of our knowledge, there are two reports on the determination of the concentration of entrectinib in biological matrix by Attwa's team (Attwa, Darwish, Alhazmi, & Kadi, ; Attwa, Kadi, Alrabiah, & Darwish, ). One method required elaborate sample preparation, greater sample volume and injection volume, and had low sensitivity (Attwa, Darwish, et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Quantification and pharmacokinetic study of entrectinib in rat plasma using ultra‐performance liquid chromatography tandem mass spectrometry

Wang

Fang

Zheng

et al. 2019

Biomedical Chromatography

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To characterize the preclinical plasma pharmacokinetics of entrectinib, a reproducible and precise assay is necessary. In this study, we developed and validated a simple ultra‐performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) method for the measurement of entrectinib using carbamazepine as the internal standard in rat plasma. Sample preparation was a simple protein precipitation with acetonitrile, then entrectinib was eluted on an Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm) using a gradient elution with a mobile phase composed of acetonitrile (A) and 0.1% formic acid in water (B). Detection was achieved using multiple‐reaction monitoring in positive ion electrospray ionization mode. The method showed good linearity over the concentration range of 1–250 ng/mL (r2 > 0.9951). The intra‐ and inter‐day precision was determined with the values of 6.3–12.9 and 2.6–6.9%, respectively, and accuracy values of 0.5–11.6%. Matrix effect, extraction recovery, and stability data all met the acceptance criteria of US Food and Drug Administration guidelines for bioanalytical method validation. The method was successfully applied to a pharmacokinetic study. In this study, we developed the complete validated method for the quantification of entrectinib in rat plasma.

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Detection and characterization of olmutinib reactive metabolites by LC–MS/MS: Elucidation of bioactivation pathways

Attwa

Kadi

2019

J of Separation Science

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Olmutinib (Olita™) is an orally bioavailable third generation epidermal growth factor receptor tyrosine kinase inhibitor. Olmutinib was approved in South Korea in May 2016 for the treatment of patients suffering from locally advanced or metastatic epidermal growth factor receptor T790M mutation‐positive non‐small cell lung cancer. Reactive olmutinib intermediates may be responsible for the severe side effects associated with the treatment. However, literature review revealed no previous reports on the structural identification of reactive olmutinib metabolites. In this work, the formation of reactive olmutinib metabolites in rat liver microsomes was investigated. Methoxylamine, glutathione, and potassium cyanide were used as capturing agents for aldehyde, iminoquinones, and iminium intermediates, respectively. The stable complexes formed were identified using liquid chromatography–tandem mass spectrometry. The major phase I metabolic pathway observed in vitro was hydroxylation of the piperazine ring. Seven potential reactive intermediates were characterized, including three iminium ions, three iminoquinones, and one aldehyde. Based on the findings, various bioactivation pathways were postulated. Hence, identifying the reactive intermediates of olmutinib that may be the cause of severe side effects can provide new insights, leading to improved treatments for patients.

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LC–MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: In vivo and in vitro metabolic investigation

Cited by 38 publications

References 23 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

Quantification and pharmacokinetic study of entrectinib in rat plasma using ultra‐performance liquid chromatography tandem mass spectrometry

Detection and characterization of olmutinib reactive metabolites by LC–MS/MS: Elucidation of bioactivation pathways

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