title: Metabolite profiling of14C-omacetaxine mepesuccinate in plasma and excreta of cancer patients.
abstract: Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72 h after a single 1.25-mg/m2subcutaneous dose of14C-omacetaxine in cancer patients. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4'-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4'-desmethyl homoharringtonine (4'-DMHHT) was the most abundant metabolites. Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.
authors.affiliation: a Department of Pharmacy and Pharmacology , Antoni Van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart , Amsterdam , The Netherlands.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Nijenhuis
authors.affiliation: a Department of Pharmacy and Pharmacology , Antoni Van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart , Amsterdam , The Netherlands.
authors.forename: Luc
authors.initials: L
authors.lastname: Lucas
authors.affiliation: a Department of Pharmacy and Pharmacology , Antoni Van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart , Amsterdam , The Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: b Nonclinical DMPK, Teva Branded Pharmaceutical R&D, Inc. , West Chester , PA , USA.
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
authors.affiliation: b Nonclinical DMPK, Teva Branded Pharmaceutical R&D, Inc. , West Chester , PA , USA.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
authors.affiliation: c Division of Clinical Pharmacology , Department of Medical Oncology, The Netherlands Cancer Institute , Amsterdam , The Netherlands and.|d Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences , Utrecht University , Utrecht , The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: a Department of Pharmacy and Pharmacology , Antoni Van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart , Amsterdam , The Netherlands.|d Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences , Utrecht University , Utrecht , The Netherlands.
authors.forename: And Jos H
authors.initials: AJ
authors.lastname: Beijnen
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000097:blood* / Q000493:pharmacokinetics; D006248:Harringtonines / Q000097:blood* / Q000493:pharmacokinetics; D000077863:Homoharringtonine; D055442:Metabolome; D009369:Neoplasms / Q000097:blood*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006248:Harringtonines; D000077863:Homoharringtonine
keywords: Disposition; homoharringtonine; mepesuccinate; metabolism; metabolite profiling; metabolites; omacetaxine; pharmacokinetics