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LC-ESI-MS/MS identification and characterization of ponatinib in vivo phase I and phase II metabolites

Mohamed W Attwa1, Adnan A Kadi2, Hany W Darwish1

  • 1Department 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.

Clinica Chimica Acta; International Journal of Clinical Chemistry
|July 4, 2018
PubMed

Insights

This study details the in vivo metabolism of ponatinib in Sprague Dawley rats. Researchers identified thirteen phase I and one phase II metabolite, revealing key metabolic pathways like piperazine ring oxidation.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Biochemistry

Background:

  • Ponatinib (Iclusig®) is a multi-targeted tyrosine kinase inhibitor (TKI) effective against BCR-ABL mutants.
  • Understanding its in vivo metabolism is crucial for its clinical application.

Purpose of the Study:

  • To investigate the in vivo metabolic profile of ponatinib in Sprague Dawley rats.
  • To characterize and identify ponatinib's phase I and phase II metabolites.

Main Methods:

  • Oral administration of ponatinib (4.7 mg/kg) to Sprague Dawley rats.
  • Urine sample collection and filtration (0.45 μm syringe filters).
  • Acetonitrile (ACN) extraction and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for metabolite identification.

Main Results:

  • Identification of thirteen in vivo phase I metabolites and one in vivo phase II metabolite.
  • Major phase I reactions included reduction, N-demethylation, hydroxylation, N-oxidation, oxidation, and amide hydrolysis.
  • Major metabolic pathways involved α-hydroxylation and α-oxidation at the piperazine ring.
  • Phase II metabolism involved glucuronidation of hydroxyl benzyl metabolites.

Conclusions:

  • This study provides the first comprehensive characterization of ponatinib's in vivo metabolites in Sprague Dawley rats.
  • The identified metabolic pathways, particularly piperazine ring modifications, are key to understanding ponatinib's pharmacokinetic profile.
  • These findings contribute valuable data for future drug development and clinical safety assessments.
Keywords:
In vivo metabolitesOxidized cyclic tertiary aminePhase separationPonatinibSprague Dawley ratsTyrosine kinase inhibitors

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