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

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.

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5004 ◽  
Author(s):  
Ali S. Abdelhameed ◽  
Mohamed W. Attwa ◽  
Adnan A. Kadi

Tepotinib (Tepmetko™, Merck) is a potent inhibitor of c-Met (mesenchymal−epithelial transition factor). In March 2020, tepotinib (TEP) was approved for use in Japan for the treatment of patients who suffered from non-small cell lung cancers (NSCLC) harboring an MET exon 14 skipping alteration and have progressed after platinum-based therapy. Practical and in silico experiments were used to screen for the metabolic profile and reactive intermediates of TEP. Knowing the bioactive center and structural alerts in the TEP structure helped in making targeted modifications to improve its safety. First, the prediction of metabolism vulnerable sites and reactivity metabolic pathways was performed using the StarDrop WhichP450™ module and the online Xenosite reactivity predictor tool, respectively. Subsequently, in silico data were used as a guide for the in vitro practical work. Second, in vitro phase I metabolites of TEP were generated from human liver microsome (HLM) incubations. Testing for the generation of unstable reactive intermediates was performed using potassium cyanide as a capturing agent forming stable cyano adduct that can be characterized and identified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Third, in silico toxicity assessment of TEP metabolites was performed, and structural modification was proposed to decrease their side effects and to validate the proposed bioactivation pathway using the DEREK software. Four TEP phase I metabolites and four cyano adducts were characterized. The reactive intermediate generation mechanism of TEP may provide an explanation of its adverse reactions. The piperidine ring is considered a structural alert for toxicity as proposed by the DEREK software and a Xenosite reactivity model, which was confirmed by practical experiments. Steric hindrance or isosteric replacement at α-carbon of the piperidine ring stop the bioactivation sequence that was confirmed using the DEREK software. More drug discovery studies can be performed using this perception permitting the design of new drugs with an increased safety profile. To our knowledge, this is the first study for the identification of in vitro phase I metabolites and reactive intermediates in addition to toxicological properties of the metabolites for TEP that will be helpful for the evaluation of TEP side effects and drug–drug interactions in TEP-treated patients.


2018 ◽  
Vol 485 ◽  
pp. 144-151 ◽  
Author(s):  
Mohamed W. Attwa ◽  
Adnan A. Kadi ◽  
Hany W. Darwish ◽  
Sawsan M. Amer ◽  
Haitham AlRabiah

RSC Advances ◽  
2017 ◽  
Vol 7 (58) ◽  
pp. 36279-36287 ◽  
Author(s):  
Adnan A. Kadi ◽  
Sawsan M. Amer ◽  
Hany W. Darwish ◽  
Mohamed W. Attwa

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.


2016 ◽  
Vol 31 (1) ◽  
pp. 140-151 ◽  
Author(s):  
Hyesoo Jeong ◽  
Soolin Kim ◽  
Jimin Lee ◽  
Jin Young Park ◽  
Wenmei Zhou ◽  
...  

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

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


2019 ◽  
Vol 6 (1) ◽  
pp. 181714 ◽  
Author(s):  
Adnan A. Kadi ◽  
Hany W. Darwish ◽  
Hatem A. Abuelizz ◽  
Thamer A. Alsubi ◽  
Mohamed W. Attwa

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.


2020 ◽  
Vol 29 (4) ◽  
pp. 2109-2130
Author(s):  
Lauren Bislick

Purpose This study continued Phase I investigation of a modified Phonomotor Treatment (PMT) Program on motor planning in two individuals with apraxia of speech (AOS) and aphasia and, with support from prior work, refined Phase I methodology for treatment intensity and duration, a measure of communicative participation, and the use of effect size benchmarks specific to AOS. Method A single-case experimental design with multiple baselines across behaviors and participants was used to examine acquisition, generalization, and maintenance of treatment effects 8–10 weeks posttreatment. Treatment was distributed 3 days a week, and duration of treatment was specific to each participant (criterion based). Experimental stimuli consisted of target sounds or clusters embedded nonwords and real words, specific to each participants' deficit. Results Findings show improved repetition accuracy for targets in trained nonwords, generalization to targets in untrained nonwords and real words, and maintenance of treatment effects at 10 weeks posttreatment for one participant and more variable outcomes for the other participant. Conclusions Results indicate that a modified version of PMT can promote generalization and maintenance of treatment gains for trained speech targets via a multimodal approach emphasizing repeated exposure and practice. While these results are promising, the frequent co-occurrence of AOS and aphasia warrants a treatment that addresses both motor planning and linguistic deficits. Thus, the application of traditional PMT with participant-specific modifications for AOS embedded into the treatment program may be a more effective approach. Future work will continue to examine and maximize improvements in motor planning, while also treating anomia in aphasia.


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