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University of Oulu

1. Lassila, T. (Toni). In vitro methods in the study of reactive drug metabolites with liquid chromatography / mass spectrometry.

Degree: 2016, University of Oulu

Abstract Reactive metabolites are believed to be responsible for rare but serious idiosyncratic adverse drug reactions (IADRs) that have led to the withdrawal of numerous drugs from the market. This has resulted in major harm to patients, economic losses for the pharmaceutical companies and represents a serious problem in drug development. Reactive metabolites can be studied by trapping them with suitable nucleophiles, most commonly with glutathione. The glutathione conjugates formed in these reactions can be analyzed with liquid chromatography mass spectrometry (LC/MS) techniques. In this study, new in vitro methods for the detection and analysis of reactive metabolites were developed. The suitability for reactive metabolite screening of different enzyme sources commonly used in vitro were compared. It was found that sub-cellular fractions yielded significantly larger amounts of glutathione-trapped reactive metabolites as compared to the amounts obtained from intact hepatocytes. Additionally, different metabolites were detected in some cases. Biomimetic metalloporphyrin catalysts were tested for their ability to produce larger amounts of glutathione-trapped metabolites relative to liver S9 fraction incubations. An increase in reactive metabolite production was observed with biomimetic models, but not all of the metabolites produced by liver S9 were observed. The glutathione conjugates of pulegone and of its metabolite menthofuran were analyzed with LC/MS/MS, and the fragmentation spectra of N- and S-/N- di-linked glutathione conjugate were interpreted in detail for the first time. These results will enable more efficient screening of reactive metabolites of furan-containing compounds. Acyl glucuronides are metabolites produced from carboxylic acid-containing compounds and can be reactive. A good correlation was found between the acyl migration half-life and the tendency of a drug to cause IADRs. The carboxylic moiety can also be metabolized to yield acyl coenzyme A (CoA) conjugates that may be more reactive than their corresponding acyl glucuronides. The formation of CoA conjugates and additional conjugates formed from them was found to be more likely with drugs that cause IADRs.

Tiivistelmä Reaktiivisten metaboliittien uskotaan olevan syypää tietyntyyppisiin harvinaisiin, mutta vakaviin idiosynkraattisiin lääkehaittavaikutuksiin, jotka ovat johtaneet useiden lääkeaineiden poistamiseen markkinoilta. Ne ovat aiheuttaneet merkittäviä haittoja potilaille, tappioita lääkeyhtiöille ja ovat vakava ongelma lääkekehityksessä. Reaktiivisia metaboliitteja voidaan tutkia vangitsemalla niitä sopivilla nukleofiileillä, yleisimmin glutationilla. Muodostuneet glutationikonjugaatit voidaan sitten analysoida nestekromatografia / massaspektrometrisin tekniikoin. Tässä tutkimuksessa kehitettiin uusia in vitro tapoja havaita ja analysoida reaktiivisia metaboliitteja. Tavallisimmin käytettyjen entsyymilähteiden soveltuvuutta testattiin reaktiivisten metaboliittien seulontaan. Solufraktioiden havaittiin tuottavan huomattavasti…

Advisors/Committee Members: Mattila, S. (Sampo), Turpeinen, M. (Miia), Tolonen, A. (Ari).

Subjects/Keywords: acyl glucuronide; glutathione trapping; liquid chromatography; mass spectrometry; reactive metabolites; asyyliglukuroni; glutationi; massaspektrometria; nestekromatografia; reaktiiviset metaboliitit

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Lassila, T. (. (2016). In vitro methods in the study of reactive drug metabolites with liquid chromatography / mass spectrometry. (Doctoral Dissertation). University of Oulu. Retrieved from http://urn.fi/urn:isbn:9789526212197

Chicago Manual of Style (16th Edition):

Lassila, T (Toni). “In vitro methods in the study of reactive drug metabolites with liquid chromatography / mass spectrometry.” 2016. Doctoral Dissertation, University of Oulu. Accessed February 24, 2021. http://urn.fi/urn:isbn:9789526212197.

MLA Handbook (7th Edition):

Lassila, T (Toni). “In vitro methods in the study of reactive drug metabolites with liquid chromatography / mass spectrometry.” 2016. Web. 24 Feb 2021.

Vancouver:

Lassila T(. In vitro methods in the study of reactive drug metabolites with liquid chromatography / mass spectrometry. [Internet] [Doctoral dissertation]. University of Oulu; 2016. [cited 2021 Feb 24]. Available from: http://urn.fi/urn:isbn:9789526212197.

Council of Science Editors:

Lassila T(. In vitro methods in the study of reactive drug metabolites with liquid chromatography / mass spectrometry. [Doctoral Dissertation]. University of Oulu; 2016. Available from: http://urn.fi/urn:isbn:9789526212197

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