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Structural evaluation of the glucuronides of morphine and formoterol using chemical derivatization with 1,2-Dimethylimidazole-4-sulfonyl chloride and LC-MSn
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
In: Rapid Communications in Mass SpectrometryArticle in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-97127OAI: oai:DiVA.org:uu-97127DiVA: diva2:171928
Available from: 2008-04-25 Created: 2008-04-25Bibliographically approved
In thesis
1. Chemical Derivatization in Combination with Liquid Chromatography Tandem Mass Spectrometry for Detection and Structural Investigation of Glucuronides
Open this publication in new window or tab >>Chemical Derivatization in Combination with Liquid Chromatography Tandem Mass Spectrometry for Detection and Structural Investigation of Glucuronides
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents novel approaches for structural investigation of glucuronides using chemical derivatization in combination with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MSn).

Today, LC-ESI-MSn is the dominant technique for quantitative as well as qualitative analyses of metabolites, due to its high sensitivity and selectivity. However, for compounds without an easily ionizable group, e.g., steroids, the sensitivity is limited. In the work presented in this thesis, a derivatization procedure forming a basic oxime significantly increased the detection sensitivity for the altrenogest glucuronide.

Furthermore, in structural evaluations of glucuronides, the limitation of LC-MSn becomes evident due to the initial neutral loss of 176 u, i.e. monodehydrated glucuronic acid, which often makes it impossible to elucidate the structures of the conjugates. To solve this problem, the main part of the work described in this thesis was devoted to chemical derivatization as a means of facilitating the determination of the site of conjugation.

For the first time, the isomeric estriol glucuronides were evaluated using a combination of three reagents 2-chloro-1-methylpyridinium iodide (CMPI), 1-ethyl-3-(3-dimethyl- aminopropyl)-carbodiimide (EDC), and 2-picolylamine (PA). Interestingly, the derivatization gave a selective fragmentation pattern leading to differentiation of the isomers.

Another derivatization reagent, 1,2-dimethylimidazole-4-sulfonyl chloride (DMISC), was also tested for the first time in structural investigations. The isomeric glucuronides of morphine, formoterol, and hydroxypropranolol were evaluated. They can all be conjugated in aliphatic as well as aromatic positions. DMISC was proven to be useful in two ways. Firstly, the morphine and formoterol glucuronides that contained a free phenol could be differentiated from those that were conjugated in the aromatic position based on different reactivity. Secondly, for the aromatic O-glucuronide of 4’-hydroxypropranolol, DMISC was proven to react with the amine. This product gave a different fragmentation pattern compared to the corresponding derivative of the aliphatic glucuronide.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 75 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 72
Pharmaceutical chemistry, Derivatization, mass spectrometry, glucuronide, drug metabolism, increased sensitivity, structural investigation, 2-chloro-1-methylpyridinium iodide (CMPI), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), 2-picolylamine (PA), 1,2-dimethylimidazole-4-sulfonyl chloride (DMISC), Farmaceutisk kemi
urn:nbn:se:uu:diva-8670 (URN)978-91-554-7178-1 (ISBN)
Public defence
2008-05-16, B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2008-04-25 Created: 2008-04-25Bibliographically approved

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