title: Identification of metabolites of fosinopril produced by human and rat liver microsomes with liquid chromatography-mass spectrometry.
abstract: Metabolic profiles of prodrug fosinopril and pharmacologically active metabolite fosinoprilat were studied using human or rat liver microsomes and S9 fractions. Metabolites were identified by ultra high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS) using electrospray ionization in the positive and negative ion mode. They were characterized by accurate MS and MS/MS spectra and based on their different fragmentation pathways. With human liver microsomes fosinopril was metabolized via hydroxylation, glucuronidation, and hydrolysis to fosinoprilat. As expected the main metabolite was fosinoprilat and it was further hydroxylated and glucuronidated. However, these metabolites were not detected after incubation of fosinoprilat with human liver microsomes, indicating that metabolic reactions occur in sequence and fosinopril is hydrolyzed after glucuronidation or hydroxylation. With the developed UHPLC/Q-TOF-MS method once or twice hydroxylated fosinopril metabolites were detected for the first time and different regioisomers were separated. It was observed that the hydrolysis of fosinopril to fosinoprilat was more efficient with rat than with human liver microsomes, and therefore more hydroxylated fosinoprilat metabolites were detected when rat liver microsomes were used. Glucuronidation of fosinopril was not observed with rat liver microsomes.
authors.affiliation: Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, P.O.Box 56, FI-00014 Helsinki, Finland; Orion Corporation ORION PHARMA, P.O.Box 65, FI-02101 Espoo, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Uutela
authors.affiliation: Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, P.O.Box 56, FI-00014 Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Monto
authors.affiliation: Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, P.O.Box 56, FI-00014 Helsinki, Finland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Iso-Mustajärvi
authors.affiliation: Made Consulting, Suonpääntie 6, FI-21500 Piikkiö, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Madetoja
authors.affiliation: Division of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, P.O.Box 56, FI-00014 Helsinki, Finland.
authors.forename: Marjo
authors.initials: M
authors.lastname: Yliperttula
authors.affiliation: Department of Forensic Medicine, Hjelt Institute, Faculty of Medicine, University of Helsinki, P.O.Box 40, FI-00014 Helsinki, Finland. Electronic address: raimo.ketola@helsinki.fi.
authors.forename: Raimo A
authors.initials: RA
authors.lastname: Ketola
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D017328:Fosinopril / Q000494:pharmacology*; D006801:Humans; D013058:Mass Spectrometry; D055432:Metabolomics; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats
chemical_list: D000959:Antihypertensive Agents; D017328:Fosinopril
keywords: Fosinopril; Fosinoprilat; Hydroxylated fosinopril metabolites; Metabolism; Q-TOF-MS; UHPLC