Belizatinib: Novel reactive intermediates and bioactivation pathways characterized by LC-MS/MS

  • J Pharm Biomed Anal. 2019 Jul 15;171:132-147. doi: 10.1016/j.jpba.2019.04.006.
Mohamed W Attwa  1 ,  Adnan A Kadi  2 ,  Hany W Darwish  3
Affiliations
  • 1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Students' University Hospital, Mansoura University, Mansoura 35516, Egypt. Electronic address: [email protected].
  • 2. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 3. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt. Electronic address: [email protected].
PMID: 30999224 DOI: 10.1016/j.jpba.2019.04.006
Abstract

Belizatinib (BZB; TSR-011) is a next-generation anaplastic lymphoma kinase inhibitor that also inhibits tropomyosin-related kinases A/B/C. In this in-vitro study, we examined the formation of reactive metabolites from BZB using rat liver microsomes or human liver microsomes in the presence of a trapping agent (potassium cyanide) to generate iminium reactive intermediates. Identification of the in vitro BZB metabolites indicated that the major in-vitro metabolic reaction involved hydroxylation of the piperidine moiety. We identified eight in-vitro phase I metabolites and three iminium reactive intermediates, suggesting two possible BZB-bioactivation pathways. We propose that the tertiary nitrogen in the piperidine ring activates the attached benzyl carbon in addition to the two α carbons inside the ring. To our knowledge, this is the first report on the structural identification of reactive metabolites derived from BZB.

Keywords
Belizatinib; Benzyl carbon bioactivation; Iminium reactive intermediates; Toxicity.
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