{"id":6306,"date":"2026-03-31T14:43:25","date_gmt":"2026-03-31T14:43:25","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/debbie-deben\/"},"modified":"2026-03-31T14:43:31","modified_gmt":"2026-03-31T14:43:31","slug":"debbie-deben","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/debbie-deben\/","title":{"rendered":"Debbie Deben"},"content":{"rendered":"","protected":false},"excerpt":{"rendered":"","protected":false},"author":8,"featured_media":6307,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-6306","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"Optimizing thiopurine therapy in Inflammatory Bowel Disease patients","samenvatting":"Inflammatoire darmziekten (Inflammatory bowel disease, IBD), bestaande uit de ziekte van Crohn (CD), colitis ulcerosa (UC) en geclassificeerde IBD (IBD-unclassified, IBD-U), is een chronische ontstekingsziekte van het maagdarmkanaal. De incidentie en prevalentie van IBD nemen wereldwijd toe, terwijl de exacte etiologie van IBD onbekend blijft. Over het algemeen wordt IBD gediagnosticeerd bij pati\u00ebnten tussen de 20 en 40 jaar oud en de meeste pati\u00ebnten hebben er hun hele leven last van. Het ziektebeloop van IBD wordt gekenmerkt door perioden van ziekteaanvallen, afgewisseld met perioden van rust. Tijdens terugvallen hebben pati\u00ebnten onder andere last van vermoeidheid, algehele malaise, buikpijn en diarree.\n\nDe thiopurinederivaten azathioprine (AZA), mercaptopurine (MP) en tioguanine (TG) zijn veelgebruikte immunosuppressiva bij de behandeling van IBD. Thiopurines hebben een langzame werking (na 8-16 weken) en zijn vooral geschikt om remissie van de ziekte te handhaven. Inductie van remissie wordt meestal bereikt door andere medicamenteuze behandelingen, zoals prednisolon of infliximab (IFX).\n\nThiopurines zijn farmacologisch inactieve geneesmiddelen die worden omgezet in actieve metabolieten. De 6-thioguanine nucleotiden (6-TGN) en de 6-methylmercaptopurine ribonucleotiden (6-MMPR) worden beschouwd als de belangrijkste actieve thiopurine metabolieten met betrekking tot respectievelijk de werkzaamheid en bijwerkingen (adverse drug reactions, ADR). Helaas komen bij thiopurine therapie relatief vaak ADR voor, die ofwel idiosyncratisch ofwel concentratie gerelateerd zijn. Tot op heden wordt het bepalen van bloedspiegels (Therapeutic Drug Monitoring, TDM) van de thiopurine metabolieten op grote schaal toegepast om de thiopurine therapie te optimaliseren. Het blijft echter een uitdaging om de juiste balans te vinden tussen effectiviteit en het vermijden van toxiciteit.\n\nHet doel van dit proefschrift was om nieuwe inzichten te verschaffen in optimalisatiestrategie\u00ebn van een thiopurine behandeling voor IBD pati\u00ebnten met de nadruk op farmacokinetiek, farmacogenetica en farmacodynamiek. Dit proefschrift bestaat uit vier verschillende delen.\n\nIn Deel I wordt een overzicht gegeven van de huidige en toekomstige perspectieven van TDM van thiopurine metabolieten. In Hoofdstuk 2 wordt een literatuuroverzicht over de farmacologie van thiopurines, de farmacogenetica en de voordelen en beperkingen van TDM bij thiopurine therapie in detail beschreven.","summary":"Inflammatory bowel disease (IBD), comprising Crohn\u2019s disease (CD), ulcerative colitis (UC) and IBD-unclassified (IBD-U), is a chronic inflammatory disease of the gastrointestinal tract. The incidence and prevalence of IBD are rising worldwide, whilst the exact etiology of IBD remains unknown. In general, IBD is diagnosed in patients between 20 and 40 years old, affecting most patients throughout their lifetime. The disease course of IBD is characterized by its relapsing and remitting character, in which flares alternate with periods of quiescent disease. During relapses, patients suffer from, amongst others, fatigue, general malaise, abdominal pain and diarrhea.\n\nThe thiopurine derivatives azathioprine (AZA), mercaptopurine (MP) and tioguanine (TG) are frequently used immune suppressive drugs in the treatment of IBD. Thiopurines have a slow onset of action (8 \u2013 16 weeks) and are particularly suitable to maintain remission. Induction of remission is generally attained by other medicinal treatments, such as prednisolone or infliximab (IFX).\n\nThiopurines are all pharmacologically inactive drugs, converted into active metabolites. The most important active thiopurine metabolites related to effectiveness and adverse drug reactions (ADRs) are considered to be the 6-thioguanine nucleotides (6-TGN) and the 6-methylmercaptopurine ribonucleotides (6-MMPR), respectively. Unfortunately, ADRs, being either idiosyncratic or concentration-related, are relatively common in thiopurine therapy. To date, therapeutic drug monitoring (TDM) of the thiopurine metabolites is widely applied to optimize thiopurine therapy. However, it remains challenging to balance effectiveness with avoidance of toxicity.\n\nThe aim of this thesis was to provide new insights into optimization strategies of thiopurine treatment for patients with IBD, focusing on pharmacokinetics, pharmacogenetics, and pharmacodynamics. This thesis contains four different sections.\n\nIn Part I, an overview of current and future perspectives on TDM of thiopurine metabolites is discussed. In Chapter 2, a literature review on the pharmacology of thiopurines, the pharmacogenetics and the advantages and limitations of TDM in thiopurine therapy are outlined in detail. While multiple enzymes are involved in the complex thiopurine metabolism, the well-studied enzyme thiopurine S-methyl transferase (TPMT) is considered to be the most important enzyme in balancing the 6-TGN and 6-MMPR metabolites. Polymorphisms in the gene encoding the TPMT enzyme can result in reduced activity or total inactivity, ultimately leading towards a shift in elevated (toxic) 6-TGN formation with reduction or absence of 6-MMPR formation. On the contrary,","auteur":"Debbie Deben","auteur_slug":"debbie-deben","publicatiedatum":"3 oktober 2025","taal":"EN","url_flipbook":"","url_download_pdf":"","url_epub":"https:\/\/ebook.proefschriftmaken.nl\/epub\/debbiedeben","ordernummer":"FTP-202603311441","isbn":"978-94-6510-735-6","doi_nummer":"","naam_universiteit":"Universiteit Maastricht","afbeeldingen":6308,"naam_student:":"","binnenwerk":"","universiteit":"Universiteit Maastricht","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/6306","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"author":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=6306"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/6306\/revisions"}],"predecessor-version":[{"id":6309,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/6306\/revisions\/6309"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/6307"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=6306"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=6306"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}