Metabolism of the MEK1/2 Inhibitor Pimasertib Involves a Novel Conjugation with Phosphoethanolamine in Patients with Solid Tumors.

Abstract

Pimasertib (AS703026 or MSC1936369B) is a selective inhibitor of MEK1/2, the mitogen-activated protein kinase (MAPK) signaling pathway, which is often dysregulated in cancer cells. Pimasertib has shown potent preclinical antitumor activity and its clinical activity is being investigated in various tumor types. In this phase I study, the disposition and biotransformation of 14C-radiolabeled pimasertib was investigated in six patients with locally advanced or metastatic solid tumors (NCT01713036). Ultra-performance liquid chromatography-mass spectrometry and radiodetection techniques were used to investigate the profiles and structures of metabolites in plasma, urine, and feces after a single oral dose of 14C-pimasertib. A total of 14 different phase I and II metabolites of 14C-pimasertib were detected, which were principally generated through oxidations and conjugations (direct and indirect); but other reactions included isomerization, N-dealkylation, deamination, and deiodination to form minor metabolites. Two major metabolites (>10% of total drug-related material), M554 and M445, were identified in plasma and urine. In feces, M445 was the primary metabolite with only trace amounts of M554 excreted. All other metabolites, including enantiomers of M445 and pimasertib, were detected to a lesser extent (<5%) in these matrices. M445 was identified as a carboxylic acid of pimasertib. M554 was identified as a novel phosphoethanolamine conjugate on the propanediol moiety of pimasertib by high-resolution mass spectrometry and multiple nuclear magnetic resonance spectroscopy techniques. To our knowledge, a phosphoethanolamine conjugate is a novel metabolite not previously described for a pharmaceutical agent and requires detailed further investigations to understand any implications.

• Authors: Holger Scheible, Friedrich Kraetzer, Andreas Marx, Andreas Johne, Elmar Wimmer
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 45 Issue 2 Pg. 174-182 (02 2017) ISSN: 1521-009X [Electronic] United States
• PMID: 27934635 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Ethanolamines
• N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide
• Protein Kinase Inhibitors
• Niacinamide
• phosphorylethanolamine
• MAP2K2 protein, human
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Adolescent
• Adult
• Aged
• Biotransformation
• Ethanolamines (metabolism)
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• MAP Kinase Signaling System (drug effects)
• Male
• Middle Aged
• Neoplasms (blood, metabolism, urine)
• Niacinamide (analogs & derivatives, metabolism, pharmacokinetics)
• Protein Kinase Inhibitors (metabolism, pharmacokinetics)
• Tissue Distribution
• Young Adult