title: 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 of14C-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 of14C-pimasertib. A total of 14 different phase I and II metabolites of14C-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.affiliation: Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany (H.S., F.K., E.W.); Central Analytics, Bio NMR and NMR Spectroscopy (A.M.) and Department of Clinical Pharmacology (A.J.), Merck KGaA, Darmstadt, Germany holger.scheible@merckgroup.com.
authors.forename: Holger
authors.initials: H
authors.lastname: Scheible
authors.affiliation: Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany (H.S., F.K., E.W.); Central Analytics, Bio NMR and NMR Spectroscopy (A.M.) and Department of Clinical Pharmacology (A.J.), Merck KGaA, Darmstadt, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kraetzer
authors.affiliation: Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany (H.S., F.K., E.W.); Central Analytics, Bio NMR and NMR Spectroscopy (A.M.) and Department of Clinical Pharmacology (A.J.), Merck KGaA, Darmstadt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Marx
authors.affiliation: Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany (H.S., F.K., E.W.); Central Analytics, Bio NMR and NMR Spectroscopy (A.M.) and Department of Clinical Pharmacology (A.J.), Merck KGaA, Darmstadt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Johne
authors.affiliation: Institute of Drug Metabolism and Pharmacokinetics, Merck KGaA, Grafing, Germany (H.S., F.K., E.W.); Central Analytics, Bio NMR and NMR Spectroscopy (A.M.) and Department of Clinical Pharmacology (A.J.), Merck KGaA, Darmstadt, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Wimmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001711:Biotransformation; D004983:Ethanolamines / Q000378:metabolism*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000378:metabolism* / Q000652:urine; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D004983:Ethanolamines; C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C005448:phosphorylethanolamine; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human