Therapeutic Drug-Monitoring of Methotrexate-Polyglutamates in Rheumatoid Arthritis

191 Pages·2014·30.72 MB·English

Therapeutic Drug-Monitoring of
Methotrexate-Polyglutamates
in Rheumatoid Arthritis
The work presented in this thesis was performed at the department of Clinical Chemistry
of the Erasmus University Medical Center, Rotterdam, The Netherlands. The work was
financially supported by the Dutch Arthritis Foundation (Reumafonds, grant no. 9-1-402).
Financial support for the publication of this thesis was kindly provided by the Dutch Arthritis
Foundation (Reumafonds) and the Erasmus University Rotterdam.
ISBN/EAN: 978-90-7138-200-0
Printed by: Gildeprint Drukkerijen - www.gildeprint.nl
All rights reserved. No part of this thesis may be reproduced or transmitted in any form or
by any means without prior permission of the author, E. den Boer, or when appropiate, of
the scientific journal in which parts of this thesis have been published.
© 2014 E. den Boer
Therapeutic Drug-Monitoring of
Methotrexate-Polyglutamates
in Rheumatoid Arthritis
Therapeutische bloedspiegel bepaling
van methotrexaat-polyglutamaten
bij reumatoïde artritis
Proefschrift
Ter verkrijging van de graad doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de rector magnificus
Prof.dr. H.A.P. Pols
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
18 juni 2014 om 13:30
door
Ethan den Boer
Geboren te Rotterdam
Promotie commissie
Promotor: Prof.dr. J. Lindemans
Overige leden: Prof.dr. I.P. Kema
Prof.dr. P.L.C.M. van Riel
Prof.dr. A.G. Vulto
Copromotoren: dr. R. de Jonge
dr. T.M. Luider
The anthropologists got it wrong when they named our species Homo sapiens (‘wise man’).
In any case it’s an arrogant and bigheaded thing to say, wisdom being one of our least
evident features. In reality, we are Pan narrans, the storytelling chimpanzee.
― Terry Pratchett, Ian Stewart and Jack Cohen - The Science of Discworld II: The Globe

Table of contents
Chapter 1 9
Introduction
Chapter 2 23
Assessment of intracellular methotrexate and methotrexate polyglutamate metabolite
concentrations in erythrocytes by ultrafast matrix-assisted laser desorption/ionization
triple quadrupole tandem mass spectrometry
Chapter 3 41
Measuring methotrexate polyglutamates in red blood cells; a new LC-MS/MS based
method
Chapter 4 57
A new U-HPLC-ESI-MS/MS based stable isotope dilution method for the detection and
quantitation of methotrexate in plasma
Chapter 5 75
Using fluorescence polarization immunoassay for determination of erythrocyte
methotrexate-polyglutamates, a quick and easy test?
Chapter 6 87
Clinical, metabolic and genetic determinants of erythrocyte methotrexate-polyglutamate
concentrations at 3 months of treatment in rheumatoid arthritis
Chapter 7 117
Effect of two dosing regimens on intracellular MTX polyglutamate accumulation in
rheumatoid arthritis patients
Chapter 8 135
Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in
rheumatoid arthritis patients
Chapter 9 153
Discussion
Addendum
Summary 174
Dutch summary / Nederlandse samenvatting 178
List of abbreviations 182
Publications 184
PhD portfolio 186
Acknowledgements / Dankwoord 188
About the Author 191

Chapter 1
Introduction
Chapter 1
10