Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors

Jackson, Klarissa D.; Durandis, Rebecca

doi:10.3390/ijms19082367

Cited by 41 publications

(40 citation statements)

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“…This indicates that not having a human CYP ortholog in zebrafish does not necessarily mean that there will be no biotransformation of drugs. Considering different β-keto designed drugs metabolites (e.g., ethylone and N-ethylpentylone), it is possible that methylone exhibits a behavior on CYP isoenzymes for zebrafish, which is similar to the action of methylone on human CYP2D6 [37,38]. Our findings for α-PVP metabolism corroborate our hypothesis because CYP2D6 has been described as the only responsible for the formation of M3 and M4 metabolites of α-PVP.…”

Section: Discussionsupporting

confidence: 84%

Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories

et al. 2020

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The aim of this study was to identify in vivo phase I metabolites of five psychoactive substances: N-ethylpentylone, ethylone, methylone, α-PVP and 4-CDC, using the in house developed experimental setup zebrafish (Danio rerio) water tank (ZWT). High-resolution mass spectrometry allowed for metabolite identification. A pilot study of reference standard collection of N-ethylpentylone from the water tank was conducted. Methods ZWT consisted in 8 fish placed in a 200 mL recipient-containing water for a single cathinone. Experiments were performed in triplicate. Water tank samples were collected after 8 h and pretreated through solid-phase extraction. Separation and accurate-mass spectra of metabolites were obtained using liquid chromatography-high resolution tandem mass spectrometry. Results Phase I metabolites of α-PVP were identified, which were formed involving ketone reduction, hydroxylation, and 2″-oxo-pyrrolidine formation. The lactam derivative was the major metabolite observed for α-PVP in ZWT. N-Ethylpentylone and ethylone were transformed into phase I metabolites involving reduction, hydroxylation, and dealkylation. 4-CDC was transformed into phase I metabolites, reported for the first time, involving N-dealkylation, N,N-bis-dealkylation and reduction of the ketone group, the last one being the most intense after 8 h of the experiment. Conclusions ZWT model indicated to be very useful to study the metabolism of the synthetic cathinones, such as N-ethylpentylone, ethylone, α-PVP and 4-CDC. Methylone seems to be a potent CYP450 inhibitor in zebrafish. More experiments are needed to better evaluate this issue. Finally, this approach was quite simple, straightforward, extremely low cost, and fast for "human-like" metabolic studies of synthetic cathinones. Keywords Synthetic cathinones • Zebrafish • In vivo metabolism • High-resolution mass spectrometry • Human-like experimental model • Reference standard collection in zebrafish water tank Electronic supplementary material The online version of this article (

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Section: Discussionsupporting

confidence: 84%

Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories

et al. 2020

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“…However, as far as TKI are concerned, very few data support the role of RM rather than the parent drug in TKI‐induced hepatotoxicity; these cases are discussed in this section. However, reporting the current state of knowledge of the entire spectrum of toxicity mechanisms at a cellular level is beyond the scope of this review …”

Section: Tki Hepatotoxicity: Evidence Of Rm Involvementmentioning

confidence: 99%

“…However, reporting the current state of knowledge of the entire spectrum of toxicity mechanisms at a cellular level is beyond the scope of this review. 5,6,55,[124][125][126][127][128] 4.1 | Crizotinib, dasatinib, erlotinib, ponatinib, regorafenib, and sorafenib…”

Section: Tki Hepatotoxicity: Evidence Of Rm Involvementmentioning

confidence: 99%

“…Albeit targeted drugs, TKI are associated with adverse effects, including organ injury, that may be serious and even life‐threatening. To date, amongst the 33 FDA‐approved TKI, 22 (67%) require warnings for liver injury in drug labeling with Black Box Warning (BBW) labels for five compounds (lapatinib, pazopanib, ponatinib, regorafenib, and sunitinib) . TKI‐induced hepatotoxicity is thus a major clinical concern and has been reviewed from a clinical perspective: 25% to 35% of clinical trial patients treated with a TKI derivative showed a low‐grade elevation in alanine and/or aspartate aminotransferases, and approximately 2% of them developed high‐grade increases in serum transaminases, with wide variability among TKI .…”

Section: Introductionmentioning

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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“…11,12) 이에 FDA에서는 심각하고 치명적인 간독성의 발 생이 보고된 TKI에 대해서 의무적으로 블랙박스 경고문 (black-box warning)을 포함시키도록 하였다. 13) TKI는…”

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Reviews on the Hepatotoxicity of Tyrosine Kinase Inhibitors

Han

Gwak

2019

Korean J Clin Pharm

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서 론 티로신 키나아제 저해제는 티로신 키나아제(tyrosine kinase, TK)를 직접적으로 억제하는 기전을 통해 항암 치료에 효과를 나타낸다. TK는 단백질 키나아제(protein kinase)의 한 종류이 며, 세포의 증식, 분화, 대사, 이동 및 세포 외 신호 전달에 의한 세포 사멸 등 여러 세포 과정에 관여하는 필수적인 조절 인자 로서, 단백질의 인산화를 촉매한다. 그러므로, TK에 돌연변이 가 일어나거나 과발현으로 인해 과도하게 활성화되는 경우, 암과 자가면역 질환의 원인이 될 수 있다. 1-3) 티로신 키나아제 저해제 중 소분자 티로신 키나아제 저해제 (tyrosine kinase inhibitor, 이하 TKI)는 경구 투여가 가능한 장 점을 가지고 있다. 이러한 TKI의 개발은 암치료에 획기적인 변화를 가져 왔다. Imatinib이 2001년 만성골수성백혈병 환자 의 80% 이상에서 완전한 세포유전학적반응을 보이는 우수한 결과를 보이며 첫 번째로 승인된 이래로, anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR)와 vascular endothelial growth factor receptor (VEGFR) 등을 포 함한 다양한 기전을 가지고 있는 30가지가 넘는 TKI가 미국 식품의약국(Food and Drug Administration, FDA)와 유럽 의 약품청(European Medicines Agency, EMA)에서 허가를 받았 다. 4)TKI는 암세포의 증식 등의 과정에 관계하는 특정 단백질 경 로를 차단하여 항암효과를 나타내기 때문에, 기존 세포 독성 ABSTRACT Background: Small-molecule tyrosine kinase inhibitors (TKIs) have had major impacts on anticancer therapy by targeting the catalytic activities of dysregulated tyrosine kinases. TKIs have not presented traditional toxicities; however, some serious adverse effects, including hepatotoxicity, have been documented in clinical trials and post-marketing surveillance. Although TKI-induced hepatotoxicity can cause severe clinical complications in patients, the underlying mechanism is still unclear. Methods: Studies on TKI-induced hepatotoxicity were identified by Pubmed search, and relevant articles were reviewed. Results: Immunoallergic reaction, cytochrome P (CYP) 450 polymorphisms, and formation of reactive metabolites are under consideration as mechanisms of TKI-induced hepatotoxicity. Host protein-drug metabolite conjugates are recognized as antigens by class II major histocompatibility complexes and are believed to cause liver injuries. Polymorphisms in CYP, which influences TKI metabolism, can slow TKI metabolism and may induce development of hepatotoxicity. The formation of reactive metabolites during drug metabolism can induce hepatotoxicity by directly causing cytotoxicity, leading to cell dysfunction, and indirect toxicity by mediating secondary immune reactions. Concurrent use of various medications with TKI can also cause hepatotoxicity by affecting drug transporter or enzyme activities. Conclusion: Periodic monitoring of patients taking TKIs and risk/benefit reassessments though post marketing surveillance are necessary to prevent hepatotoxicity.

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Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors

Cited by 41 publications

References 84 publications

Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories

Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories

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

Reviews on the Hepatotoxicity of Tyrosine Kinase Inhibitors

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