title: Advances in high-resolution MS and hepatocyte models solve a long-standing metabolism challenge: the loratadine story.
abstract: Loratadine (LOR, Claritin(®)) is a long-acting antihistamine used to treat allergic rhinitis. The major active human metabolite, desloratadine (DL, Clarinex(®)), is extensively metabolized to 3-hydroxydesloratadine (3-OH-DL) (M40) and subsequently glucuronidated before elimination. This study revealed the ability of a novel, long-term hepatocyte micropatterned co-culture (MPCC) model to generate in vivo metabolites. Metabolites were detected and characterized using non-targeted MS/MS(ALL) with SWATH™ acquisition by a UHPLC-Q-TOF system. Results & methodology: Human MPCCs extensively metabolized LOR and formed 3-OH-DL-glucuronide (M13). Cross-species comparisons revealed monkey- and rat-specific metabolites with gender-specific DL-pyridine-N-oxide formation in male rats. These results demonstrate a first for an in vitro hepatocyte model to generate circulating metabolites of LOR and detect species-specific differences. Early focus on human metabolites could have spared characterization of nonhuman metabolites in preclinical species.
authors.affiliation: Ascendance Biotechnology, Inc., Medford, MA, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Aratyn-Schaus
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: Ragu
authors.initials: R
authors.lastname: Ramanathan
mesh_terms: D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018920:Coculture Techniques / Q000379:methods; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000378:metabolism*; D006801:Humans; D017336:Loratadine / Q000031:analogs & derivatives* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051381:Rats; D013045:Species Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D020719:Glucuronides; D039563:Histamine H1 Antagonists, Non-Sedating; C482880:3-hydroxydesloratadine; D017336:Loratadine
keywords: LC–MS; SWATH; metabolism