title: Identification of domperidone metabolites in plasma and urine of gastroparesis patients with LC-ESI-MS/MS.
abstract: Domperidone is a prokinetic agent used to treat gastroparesis. Previous studies reported oxidative metabolites of domperidone, detected by radiometric high-performance liquid chromatography or single quadrupole mass spectrometric techniques. Our aim was to identify domperidone Phase I and Phase II metabolites using liquid chromatography combined with electrospray ionization-enabled tandem mass spectrometry. Domperidone metabolites were identified in the plasma and urine of 11 gastroparesis patients currently being treated with domperidone. In addition, oxidative and conjugative metabolites of domperidone were characterized in human liver subcellular fractions. Seven metabolites were detected in vivo. Domperidone was metabolized to two mono-hydroxylated metabolites (M1 and M2), a de-alkylated metabolite (M5) and a di-hydroxylated metabolite (M7). The mono-hydroxylated metabolites were further glucuronidated to M8, M9 and sulfated to M11. To the best of our knowledge, M7, M8, M9 and M11 have not been reported previously. Five additional metabolites were identified in vitro in human subcellular fractions which comprise two additional mono-hydroxylated metabolites (M3 and M4), an alcohol metabolite (M6) possibly formed from an aldehyde intermediate, and other conjugative metabolites (M10 and M12). M6, M10 and M12 have not been characterized previously. In total, 12 domperidone metabolites including 7 new metabolites were identified in the present study. These results allow a better understanding of domperidone disposition in humans.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy , Philadelphia, PA , USA .
authors.forename: Amir S
authors.initials: AS
authors.lastname: Youssef
authors.forename: Upendra A
authors.initials: UA
authors.lastname: Argikar
authors.forename: Murali
authors.initials: M
authors.lastname: Pathikonda
authors.forename: Henry P
authors.initials: HP
authors.lastname: Parkman
authors.forename: Swati
authors.initials: S
authors.lastname: Nagar
mesh_terms: D000328:Adult; D000368:Aged; D002853:Chromatography, Liquid / Q000379:methods*; D004294:Domperidone / Q000097:blood* / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D005260:Female; D018589:Gastroparesis / Q000097:blood* / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D055815:Young Adult
chemical_list: D004294:Domperidone