scholarly journals LC-MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling

RSC Advances ◽  
2017 ◽  
Vol 7 (58) ◽  
pp. 36279-36287 ◽  
Author(s):  
Adnan A. Kadi ◽  
Sawsan M. Amer ◽  
Hany W. Darwish ◽  
Mohamed W. Attwa
Keyword(s):  
Phase I ◽  
Metabolic Profiling ◽  
Reactive Intermediates ◽  
Reactive Metabolites ◽  
Iminium Ions

Using LC-MS/MS, six phase I foretinib metabolites in addition to four potential reactive metabolites, two aldehydes and two iminium ions, were detected and the bioactivation pathways were proposed.

scholarly journals Reactive intermediates in copanlisib metabolism identified by LC-MS/MS: phase I metabolic profiling

RSC Advances ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 6409-6418 ◽  
Author(s):  
Haitham AlRabiah ◽  
Adnan A. Kadi ◽  
Mohamed W. Attwa ◽  
Ali S. Abdelhameed ◽  
Gamal A. E. Mostafa
Keyword(s):  
Phase I ◽  
Metabolic Profiling ◽  
Hematological Malignancies ◽  
Kinase Inhibitor ◽  
Reactive Intermediates ◽  
Phosphoinositide 3 Kinase

Copanlisib (CNB; Aliqopa™) is a novel, intravenous phosphoinositide 3-kinase inhibitor used to treat various solid and hematological malignancies.

scholarly journals Phase I metabolic profiling and unexpected reactive metabolites in human liver microsome incubations of X-376 using LC-MS/MS: bioactivation pathway elucidation and in silico toxicity studies of its metabolites

RSC Advances ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 5412-5427 ◽  
Author(s):  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
Ali S. Abdelhameed
Keyword(s):  
Phase I ◽  
Metabolic Profiling ◽  
In Silico ◽  
Human Liver ◽  
Liver Microsome ◽  
Human Liver Microsome ◽  
Reactive Metabolites ◽  
Toxicity Studies ◽  
Pyridazine Ring ◽  
In Silico Toxicity

Metabolites of X-376 were characterized by LC-MS/MS. Pyridazine ring and dichloro-phenyl groups were bioactivated by novel pathways.

scholarly journals Identification of reactive intermediate formation and bioactivation pathways in Abemaciclib metabolism by LC–MS/MS: in vitro metabolic investigation

2019 ◽  
Vol 6 (1) ◽  
pp. 181714 ◽  
Author(s):  
Adnan A. Kadi ◽  
Hany W. Darwish ◽  
Hatem A. Abuelizz ◽  
Thamer A. Alsubi ◽  
Mohamed W. Attwa
Keyword(s):  
Phase I ◽  
Metabolic Profiling ◽  
Kinase Inhibitor ◽  
Liver Microsomes ◽  
Potassium Cyanide ◽  
Intermediate Formation ◽  
Reactive Intermediates ◽  
Stable Complex ◽  
Rat Liver Microsomes

Abemaciclib (Verzenio ® ) is approved as a tyrosine kinase inhibitor (TKI) for breast cancer treatment. In this study, in vitro phase I metabolic profiling of Abemaciclib (ABC) was done using rat liver microsomes (RLMs). We checked the formation of reactive intermediates in ABC metabolism using RLMs in the presence of potassium cyanide (KCN) that was used as a capturing agent for iminium reactive intermediates forming a stable complex that can be characterized by LC–MS/MS. Nine in vitro phase I metabolites and three cyano adducts were identified. The metabolic reactions involved in the formation of these metabolites and adducts are reduction, oxidation, hydroxylation and cyanide addition. The bioactivation pathway was also proposed. Knowing the electrodeficient bioactive centre in ABC structure helped in making targeted modifications to improve its safety and retain its efficacy. Blocking or isosteric replacement of α-carbon to the tertiary nitrogen atoms of piperazine ring can aid in reducing toxic side effects of ABC. No previous articles were found about in vitro metabolic profiling for ABC or structural identification of the formed reactive metabolites for ABC.

scholarly journals Identification and characterization of in silico, in vivo, in vitro, and reactive metabolites of infigratinib using LC-ITMS: bioactivation pathway elucidation and in silico toxicity studies of its metabolites

RSC Advances ◽  
2020 ◽  
Vol 10 (28) ◽  
pp. 16231-16244 ◽  
Author(s):  
Nasser S. Al-Shakliah ◽  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
Haitham AlRabiah
Keyword(s):  
In Silico ◽  
Reactive Intermediates ◽  
Reactive Metabolites ◽  
Laboratory Work ◽  
Iminium Ions ◽  
In Silico Toxicity ◽  
Identification And Characterization

An in silico web designer tool was utilized to guide laboratory work for infigratinib metabolism. Sixteen metabolites of infigratinib and seven reactive intermediates (three iminium ions and four 1,4 benzoquinones) were characterized using LC-ITMS.

Oxypeucedanin is a mechanism-based inactivator of CYP2B6 and CYP2D6

2021 ◽  
Vol 22 ◽  
Author(s):  
Kehan Zhang ◽  
Yilin Li ◽  
Yao Fu ◽  
Tiantian Cui ◽  
Qian Wang ◽  
...  
Keyword(s):  
Pain Relief ◽  
Liver Microsomes ◽  
Reactive Intermediates ◽  
Enzyme Inactivation ◽  
Time Dependent ◽  
Reactive Metabolites ◽  
Angelica Dahurica ◽  
Dependent Inhibition ◽  
Microsomal Incubation

Background: Herbal medicine Angelica dahurica is widely employed for the treatment of rheumatism and pain relief in China. Oxypeucedanin is a major component of the herb. Objectives : The objectives of this study are aimed at the investigation of mechanism-based inactivation of CYP2B6 and CYP2D6 by oxypeucedanin, characterization of the reactive metabolites associated with the enzyme inactivation, and identification of the P450s participating in the bioactivation of oxypeucedanin. Methods : Oxypeucedanin was incubated with liver microsomes or recombinant CYPs2B6 and 2D6 under designed conditions, and the enzyme activities were measured by monitoring the generation of the corresponding products. The resulting reactive intermediates were trapped with GSH and analyzed by LC-MS/MS. Results : Microsomal incubation with oxypeucedanin induced a time-, concentration-, and NADPH-dependent inhibition of CYPs2B6 and 2D6 with kinetic values of KI/kinact 1.82 µM/0.07 min-1 (CYP2B6) and 8.47 µM/0.044 min-1 (CYP2D6), respectively. Ticlopidine and quinidine attenuated the observed time-dependent enzyme inhibitions. An epoxide and/or γ-ketoenal intermediate(s) derived from oxypeucedanin was/were trapped in microsomal incubations. CYP3A4 was the primary enzyme involved in the bioactivation of oxypeucedanin. Conclusion : Oxypeucedanin was a mechanism-based inactivator of CYP2B6 and CYP2D6. An epoxide and/or γ-ketoenal intermediate(s) may be responsible for the inactivation of the two enzymes.

scholarly journals LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways

RSC Advances ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 1182-1190 ◽  
Author(s):  
Adnan A. Kadi ◽  
Mohamed W. Attwa ◽  
Hany W. Darwish
Keyword(s):  
Phase I ◽  
Reactive Intermediates ◽  
Piperidine Ring ◽  
Esi Ms

Four phase I BGB metabolites and three cyano adducts for BGB were detected using LC-MS/MS. The piperidine ring was found to be responsible for BGB bioactivation and the bioactivation pathways are proposed.

scholarly journals The chemistry of amine radical cations produced by visible light photoredox catalysis

2013 ◽  
Vol 9 ◽  
pp. 1977-2001 ◽  
Author(s):  
Jie Hu ◽  
Jiang Wang ◽  
Theresa H Nguyen ◽  
Nan Zheng
Keyword(s):  
Visible Light ◽  
Radical Cations ◽  
Reactive Intermediates ◽  
Visible Light Photocatalysis ◽  
Photoredox Catalysis ◽  
Iminium Ions ◽  
Distonic Ions ◽  
Synthetic Intermediates

Amine radical cations are highly useful reactive intermediates in amine synthesis. They have displayed several modes of reactivity leading to some highly sought-after synthetic intermediates including iminium ions, α-amino radicals, and distonic ions. One appealing method to access amine radical cations is through one-electron oxidation of the corresponding amines under visible light photoredox conditions. This approach and subsequent chemistries are emerging as a powerful tool in amine synthesis. This article reviews synthetic applications of amine radical cations produced by visible light photocatalysis.

LC-MS/MS reveals the formation of reactive ortho -quinone and iminium intermediates in saracatinib metabolism: Phase I metabolic profiling

2018 ◽  
Vol 482 ◽  
pp. 84-94 ◽  
Author(s):  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
Hany W. Darwish ◽  
Haitham Alrabiah
Keyword(s):  
Phase I ◽  
Metabolic Profiling

scholarly journals Reactive intermediates in naquotinib metabolism identified by liquid chromatography-tandem mass spectrometry: phase I metabolic profiling

RSC Advances ◽  
2019 ◽  
Vol 9 (18) ◽  
pp. 10211-10225 ◽  
Author(s):  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
Haitham AlRabiah ◽  
Hany W. Darwish
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Metabolic Profiling ◽  
Human Liver ◽  
Liver Microsomes ◽  
Reactive Intermediates ◽  
Tandem Mass ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

LC-MS/MS was used to screen for in vitro metabolites of NQT formed during incubation with human liver microsomes (HLMs) and then evaluated the generation of reactive electrophiles using capturing agents.

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