Effect of selected ABC-drug transporters on anticancer drug disposition in vitro and in vivo

283 Pages·2013·7.38 MB·English

Effect of selected ABC-drug transporters
on anticancer drug disposition in vitro and in vivo
Serena Marchetti
ISBN: 978-94-6108-559-7
Lay-out and printed by: Gildeprint - Enschede
Cover design: S. Leijen & S. Marchetti.
Coverpicture: Serena’s FIAT 500.
Effect of selected ABC-drug transporters
on anticancer drug disposition in vitro and in vivo
Effect van specifieke ABC-geneesmiddeltransporters op de farmacokinetiek van
antikankermiddelen in vitro en in vivo.
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor
aan de Universiteit Utrecht
op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen
op donderdag 5 december 2013 des ochtends te 10.30 uur
door
Serena Marchetti
geboren op 9 juni 1974 te Pescia, Italië
Promotoren:
Prof. dr. J.H.M. Schellens
Prof. dr. R. Mazzanti
The research described in this thesis was performed at the department of Experimental
Therapy of the Netherlands Cancer Institute, Amsterdam, the Netherlands.
Aan mijn ouders

ContEntS
Chapter 1: Introduction 9
Chapter 2: Concise review: Clinical relevance of drug-drug and herb-drug 15
interactions mediated by the ABC transporter ABCB1 (MDR1,
P-glycoprotein).
Chapter 3: Clinical relevance: drug-drug interactions, pharmacokinetics, 37
pharmacodynamics and toxicity.
Chapter 4: Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, 155
and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro
and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/-
(triple-knockout) and wild-type mice.
Chapter 5: In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) 169
by breast cancer resistance protein, P-glycoprotein, and multidrug
resistance protein 2.
Chapter 6: In vivo implications of BCRP/P-gp deletion on the pharmacokinetics 181
of gimatecan (7-t-butoxyiminomethylcamptothecin).

Chapter 7: Abcc4 together with Abcb1 and Abcg2 form a robust co-operative drug 191
efflux system that restricts the brain entry of camptothecin analogs.
Clin Cancer Res 2013;19:2084-2095.
Chapter 8: Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on 209
the disposition, brain accumulation and myelotoxicity of the aurora
kinase B inhibitor AZD1152 and its active form AZD1152-hydroxy-QPA.

Chapter 9: Effect of the drug transporters ABCB1, ABCC2 and ABCG2 on the 227
disposition and brain accumulation of the taxane analog BMS- 275183.
Chapter 10: The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport 247
and CYP3A metabolism of imatinib mesylate.
Cancer Chemother Pharmacol 2007;59:855-60.
Chapter 11: Conclusions & Perspectives 257

Appendix: Chemical structures of studied lead molecules in this thesis 268
Summary 271
Nederlandse samenvatting (Dutch summary) 274
Dankwoord (aknowledgements) 278
Curriculum Vitae 280
List of publications 282

1
General introduction
Studies described in the thesis that is lying in front of you aim to address the possible
implications of selected ABC-drug transporters on the disposition of a number of important
anticancer drugs. Although variability in drug disposition has been known for as long as
pharmacological studies supported drug development and clinical therapeutics general
molecular pharmacological concepts explaining the given interpatient variation in drug
disposition have been lacking for many decades. Firm expansion on the knowledge of
drug disposition was ignited by the discovery of the first identified drug transporter
P-glycoprotein (Pgp; ABCB1), or permeability glycoprotein, in the hallmark publication of
Juliano & Ling in 1976 [1]. They identified that this is a 170 kD transmembrane protein that,
when expressed, enables cells to become resistant to a range of well known anticancer
drugs. Later it was discovered that Pgp extrudes drugs from the inside of the cell to the
extracellular compartment at the cost of ATP. Further studies identified that efflux by Pgp
could be inhibited by verapamil [2], which would form the basis for the understanding of
the concept of drug-drug interactions (DDIs) in vitro as well as in vivo mediated by Pgp and
other later identified drug transporter proteins. This knowledge has translated in a first
clinical trial aiming to overcome tumor unresponsiveness by co-administration of a Pgp
inhibitor and a Pgp substrate drug doxorubicin, as it had been identified that a range of
solid tumors and hematological malignancies expressed Pgp a possible cause of so-called
multidrug resistance [3]. Following this hallmark trial, improving this concept has been
pursued in the laboratory and the clinic for a couple of decades. Despite the vast increase
in knowledge of the family of drug transporters, the identification of a range of naturally
occurring Pgp inhibiting substrate molecules and chemical synthesis of novel effective
inhibitors clinical benefit of this concept turned out to be meager. Disappointingly, no
combination of Pgp substrate anticancer drug plus Pgp inhibitor has shown a positive
benefit/risk in pivotal studies and the concept has been abandoned almost completely
for a number of reasons, of which discussion is considered beyond the scope of this
introductory chapter as well as of this thesis as a whole. Knowledge of the field further
deepened substantially by cloning and sequencing of the MDR (i.e. Multi Drug Resistance;
ABCB family) gene encoding Pgp in 1986 [4]. Subsequently, identification of normal tissue
expression of Pgp boosted research directed at unraveling the potential influence of Pgp
on tissue distribution of affected substrate drugs [5]. Discovery of another family of drug
transporters, the Multidrug Resistance (-associated) Protein (MRP) family in 1992 was
another important event further shaping the landscape of drug transporters [6]. In the
decade following this landmark discovery in the drug transporter field new families of
drug transporters were identified and molecularly and pharmacologically characterized,
including the Breast Cancer Resistance Protein (BCRP; ABCG2) [7]. The family members of
the ABC-(i.e. ATP-Binding Cassette) drug transporters have now all been identified and
for further details the reader is referred to recent reviews, including chapters two and
three of this thesis [8,9], and websites, for example http://www.ncbi.nlm.nih.gov/books/
NBK31/ & http://www.genenames.org/. Besides discovery of all colors of the pallet of ABC-
drug transporters valuable novel tools were established to enable studying the in vivo
pharmacological effects of ABC-drug transporters of which the first one was the mdr1a
Pgp knockout mouse [10].
It is with this as a background that studies described in the individual chapters of this
thesis should be read.
10 | Chapter 1