Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

In vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS

Version 1 : Received: 15 May 2023 / Approved: 15 May 2023 / Online: 15 May 2023 (10:28:28 CEST)

A peer-reviewed article of this Preprint also exists.

Al-Shakliah, N.S.; A. Kadi, A.; Abuelizz, H.A.; Al-Salahi, R. In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS. Separations 2023, 10, 353. Al-Shakliah, N.S.; A. Kadi, A.; Abuelizz, H.A.; Al-Salahi, R. In Vitro and Reactive Metabolites Investigation of Metabolic Profiling of Tyrosine Kinase Inhibitors Dubermatinib in HLMs by LC–MS/MS. Separations 2023, 10, 353.

Abstract

Dubermatinib (DMB, TP-0903), a benzenesulfonamide, is an inhibitor of the tyrosine kinase AXL, which is a member of the TAM family, and can prevent GAS6-mediated activation of AXL in cancer cells. Patients with previously treated chronic lymphocytic leukemia are being studied in phase I/II clinical trials to determine its antineoplastic potential (CLL). In the current work, the reactive intermediates of DMB were studied using liquid chromatography-mass spectrometry (LC-MS). Human liver microsomes (HLMs) were exposed to dimethylbenzene in a laboratory setting, and the resulting metabolites were collected through protein precipitation. Intense reactivity toward nucleophilic macromolecules was seen in the metabolites of the piperazine and pyrimidine rings in DMB, iminium and 2,5-quinone-imine, respectively. To assess the toxicities of the possibly reactive metabolites, DMB was incubated with HLMs in the presence of 1.0 mM KCN and 1.0 mM glutathione. The DMB metabolites found by LC-MS/MS were seven in vitro phase I metabolites, three cyano adducts, and two GSH conjugates. Phase I in vitro metabolic reactions included N-demethylation, hydroxylation, and dechlorination. The in vitro metabolism of DMB and the metabolites it produces have not been studied before.

Keywords

N-methyl piperazine; Dubermatinib; In vitro metabolites; Cyano adducts; GSH conjugate; Xe-nosite reactivity model

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

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