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In vivo investigation of brain and systemic ketobemidone metabolism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2010 (English)In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 135, no 2, 405-413 p.Article in journal (Refereed) Published
Abstract [en]

Ketobemidone metabolites have previously been identified in urine and plasma; here we show, for the first time, that norketobemidone and ketobemidone N-oxide are present in in vivo microdialysate from rat brain (striatum) after reverse microdialysis, suggesting striatal metabolism of ketobemidone. Ketobemidone metabolites were also identified in in vivo microdialysate samples from brain and blood, as well as in urine from rats, after subcutaneous administration of ketobemidone. Three Phase I metabolites (norketobemidone, ketobemidone N-oxide and hydroxymethoxyketobemidone) and three Phase II metabolites (glucuronic acid conjugates of ketobemidone, norketobemidone and hydroxymethoxyketobemidone) were identified in the microdialysates after subcutaneous administration. Coupled capillary liquid chromatography tandem mass spectrometry (LC-MS/MS) and SPE (boronate)-MS/MS were utilized for the analysis of the biological samples. The Phase I metabolites were identified by comparing the retention times and tandem mass spectra of the microdialysates with synthetic standards. The Phase II metabolites were identified by determination of exact masses and by comparing the tandem mass spectra of the microdialysates with those of synthetic standards for the aglycones. Hydroxyketobemidone, a catechol-type Phase I metabolite, was selectively isolated by solid-phase boronate-complexation but identified in urine alone. This work demonstrated that the in vivo microdialysis technique in combination with LC-MS/MS can be used to study the local metabolism of a drug in the brain.

Place, publisher, year, edition, pages
2010. Vol. 135, no 2, 405-413 p.
Keyword [en]
HPLC-MS/MS, hydrogen/deuterium exchange, N-oxidation, Clemastine, metabolites
National Category
Pharmaceutical Sciences Medicinal Chemistry
Research subject
Analytical Pharmaceutical Chemistry; Pharmaceutical Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-124166DOI: 10.1039/b917940bISI: 000273921800024PubMedID: 20098777OAI: oai:DiVA.org:uu-124166DiVA: diva2:317181
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved

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