Drug transporters Volume 2 Recent advances and emerging technologies

by Glynis Nicholls, Glynis Nicholls, Kuresh Youdim,

Drug transporters Volume 2 Recent advances and emerging technologies Understanding and quantifying the effects of membrane transporters within the human body is essential for modulating drug safety and drug efficacy The first volume comprehensively reviewed current knowledge and techniques in the transporter sciences and their relations to drug metabolism and pharmacokinetics In this second volume on Drug Transporters emphasis is placed on emerging sciences and technologies highlighting potential areas for future advances within the drug transporter field

Publisher : Royal Society of Chemistry

Author : Glynis Nicholls, Glynis Nicholls, Kuresh Youdim, David Thurston, David Fox, Bruno Stieger, Hideyuki Saito, David Dickens, Lena Gustavsson, Pradeep Sharma, Nico Scheer, Varma Manthena, Silke Simon, Susan Cole, Nick Plant, Ichiro Leiri, David Marcus, Bente Steffansen, Karelle Menochet, John Keogh, Aki

ISBN : 9781782628668

Year : 2016

Language: en

File Size : 3.37 MB

Category : Used Textbooks

Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP001

Drug Transporters

Volume 2: Recent Advances and Emerging Technologies

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RSC Drug Discovery Series
Editor-in-chief
Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP001

Professor David Thurston, King’s College, London, UK

Series Editors:
Professor David Rotella, Montclair State University, USA
Professor Ana Martinez, Centro de Investigaciones Biologicas-CSIC, Madrid,
Spain
Dr David Fox, Vulpine Science and Learning, UK

Advisor to the Board:
Professor Robin Ganellin, University College London, UK

Titles in the Series:
1:
2:
3:
4:
5:
6:
7:
8:
9:
10:
11:
12:
13:
14:
15:
16:
17:
18:
19:
20:
21:
22:
23:
24:
25:
26:
27:
28:
29:
30:

Metabolism, Pharmacokinetics and Toxicity of Functional Groups
Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
Accounts in Drug Discovery
New Frontiers in Chemical Biology
Animal Models for Neurodegenerative Disease
Neurodegeneration
G Protein-Coupled Receptors
Pharmaceutical Process Development
Extracellular and Intracellular Signaling
New Synthetic Technologies in Medicinal Chemistry
New Horizons in Predictive Toxicology
Drug Design Strategies: Quantitative Approaches
Neglected Diseases and Drug Discovery
Biomedical Imaging
Pharmaceutical Salts and Cocrystals
Polyamine Drug Discovery
Proteinases as Drug Targets
Kinase Drug Discovery
Drug Design Strategies: Computational Techniques and Applications
Designing Multi-Target Drugs
Nanostructured Biomaterials for Overcoming Biological Barriers
Physico-Chemical and Computational Approaches to Drug Discovery
Biomarkers for Traumatic Brain Injury
Drug Discovery from Natural Products
Anti-Inflammatory Drug Discovery
New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
Drug Discovery for Psychiatric Disorders
Organic Chemistry of Drug Degradation
Computational Approaches to Nuclear Receptors

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31: Traditional Chinese Medicine
32: Successful Strategies for the Discovery of Antiviral Drugs
33: Comprehensive Biomarker Discovery and Validation for Clinical
Application
34: Emerging Drugs and Targets for Parkinson’s Disease
35: Pain Therapeutics; Current and Future Treatment Paradigms
36: Biotherapeutics: Recent Developments using Chemical and
Molecular Biology
37: Inhibitors of Molecular Chaperones as Therapeutic Agents
38: Orphan Drugs and Rare Diseases
39: Ion Channel Drug Discovery
40: Macrocycles in Drug Discovery
41: Human-based Systems for Translational Research
42: Venoms to Drugs: Venom as a Source for the Development of Human
Therapeutics
43: Carbohydrates in Drug Design and Discovery
44: Drug Discovery for Schizophrenia
45: Cardiovascular and Metabolic Disease: Scientific Discoveries and New
Therapies
46: Green Chemistry Strategies for Drug Discovery
47: Fragment-Based Drug Discovery
48: Epigenetics for Drug Discovery
49: New Horizons in Predictive Drug Metabolism and Pharmacokinetics
50: Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis,
Evaluation
51: Nanomedicines: Design, Delivery and Detection
52: Synthetic Methods in Drug Discovery: Volume 1
53: Synthetic Methods in Drug Discovery: Volume 2
54: Drug Transporters: Volume 1: Role and Importance in ADME and Drug
Development
55: Drug Transporters: Volume 2: Recent Advances and Emerging
Technologies

How to obtain future titles on publication:
A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.

For further information please contact:
Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: þ44 (0)1223 420066, Fax: þ44 (0)1223 420247,
Email: [email protected]
Visit our website at www.rsc.org/books

Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP001

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Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP001

Drug Transporters
Volume 2: Recent Advances and Emerging
Technologies

Edited by

Glynis Nicholls
Independent Consultant, Wem, Shropshire, UK
Email: [email protected]

Kuresh Youdim
F. Hoffman-La Roche AG, Basel, Switzerland
Email: [email protected]

Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP001

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RSC Drug Discovery Series No. 55
Print ISBN: 978-1-78262-866-8
Two volume set print ISBN: 978-1-78262-867-5
PDF eISBN: 978-1-78262-870-5
EPUB eISBN: 978-1-78262-871-2
ISSN: 2041-3203
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2016
All rights reserved
Apart from fair dealing for the purposes of research for non-commercial purposes or for
private study, criticism or review, as permitted under the Copyright, Designs and Patents
Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not
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the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning
reproduction outside the terms stated here should be sent to The Royal Society of
Chemistry at the address printed on this page.
The RSC is not responsible for individual opinions expressed in this work.
The authors have sought to locate owners of all reproduced material not in their own
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Published by The Royal Society of Chemistry,
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For further information see our web site at www.rsc.org
Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK

Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP007

Preface
In this second volume of Drug Transporters, the focus is on the emerging
sciences and technologies that are currently being investigated within
this area. The fundamental concepts of transporter sciences, and the current
methods and tools employed within the pharmaceutical industry to
determine the impact of membrane transporters on drug safety and efficacy,
are covered extensively in Drug Transporters: Volume 1: Role and Importance in
ADME and Drug Development and hence are not included to any great extent
in this volume. Readers are referred to the previous volume for information
on those topics. The emphasis here is on areas where research is ongoing
but is not necessarily part of routine investigations, areas that are often
changing rapidly as knowledge expands. This current (2016) overview thus
gives an indication of where opportunities may exist for substantial advances
within the drug transporter field in the future. Where possible, reference is
also made to any available recent reviews for the interested reader. Topics in
this volume range from factors that may impact transporter form and
function (regulation of expression, enzyme–transporter interplay and pharmacogenomics) through to more practical approaches to improve our
understanding of transporter-mediated interactions (using microfluidics,
proteomics, in vivo imaging and bioinformatics/cheminformatics). Transporters in other organs and tissues of the body, not covered in Volume 1 of
the book, are also briefly discussed. We hope that this volume serves to
illustrate not only how the transporter field is progressing in many different
areas, but also how our knowledge is still incomplete, with much still to
be done.
As with the first volume, this part of the book could only be achieved
through collaboration with experts who have chosen to specialize in specific
areas of science and we remain deeply indebted to them, for both sharing
their insights in their chosen fields and for their continued commitment to
RSC Drug Discovery Series No. 55
Drug Transporters: Volume 2: Recent Advances and Emerging Technologies
Edited by Glynis Nicholls and Kuresh Youdim
r The Royal Society of Chemistry 2016
Published by the Royal Society of Chemistry, www.rsc.org

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viii

Preface

our book, despite their ongoing workloads. Its success required the input of
an extensive and widely separated group of scientists and we sincerely hope
that their efforts will translate into a volume that is referred to by many
people in the coming years, in conjunction with the first volume of
Drug Transporters.
Glynis Nicholls
Kuresh Youdim

Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP009

Acknowledgements
The editors would like to thank the following people for their input into
reviewing the chapters of Drug Transporters: Volume 2: Recent Advances and
Emerging Technologies:
Prof. Per Artursson and Dr Fabienne Gaugaz (Uppsala University) for their
review of Chapter 3.
¨r Nordell and Dr Constanze Hilgendorf (AstraZeneca) for their review
Dr Pa
of Chapter 4.
Dr Jose Ulloa (Bioxydyn Ltd) for his review of Chapter 6.
Dr Marco Berrera (Roche) for his review of Chapter 7.

RSC Drug Discovery Series No. 55
Drug Transporters: Volume 2: Recent Advances and Emerging Technologies
Edited by Glynis Nicholls and Kuresh Youdim
r The Royal Society of Chemistry 2016
Published by the Royal Society of Chemistry, www.rsc.org

ix

Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP010

Abbreviations
ABC
ABCB
ABCB1
ABCB11
ABCC
ABCC2
ABCG
ABCG2
ADE
ADME
ADMET
ADR
AhR
AMP
API
ARNT
ASBT
ATP
AUC
AUMC
BA
BBB
BCRP
BCS
BCSFB
BDDCS

Adenosine triphosphate (ATP)-binding cassette transporter
(gene superfamily)
ATP-binding cassette gene subfamily B
Gene encoding MDR1 or P-gp
Gene encoding BSEP
ATP-binding cassette gene subfamily C
Gene encoding MRP2
ATP-binding cassette gene subfamily G
Gene encoding BCRP
Absorption, distribution and elimination
Absorption, distribution, metabolism and elimination
Absorption, distribution, metabolism, elimination and
toxicity
Adverse drug reaction
Aryl hydrocarbon receptor
Adenosine monophosphate
Active pharmaceutical ingredient
Aryl hydrocarbon nuclear translocator
Apical sodium dependent bile acid transporter
Adenosine triphosphate
Area under curve
Area under the first order moment curve
Bioavailability
Blood–brain barrier
Breast cancer resistance protein (gene ABCG2)
Biopharmaceutics classification system
Blood–cerebrospinal fluid barrier
Biopharmaceutics drug disposition classification system

RSC Drug Discovery Series No. 55
Drug Transporters: Volume 2: Recent Advances and Emerging Technologies
Edited by Glynis Nicholls and Kuresh Youdim
r The Royal Society of Chemistry 2016
Published by the Royal Society of Chemistry, www.rsc.org

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Published on 10 August 2016 on http://pubs.rsc.org | doi:10.1039/9781782628705-FP010

Abbreviations

BEI
BLEC
BRB
BSEP
Caco-2
CAR
CCK8
CDF
CFTR
CHMP
CHO
ciPTEC
CIS-RR
CL or Cl
CLae
CLbile
CLd
CLefflux
CLi/CLo
CLint
CLpassive
CLren
CLuptake
Cmax
Cmedia
CNS
CNT
CNV
Co-med
CMVs
CoMFA
CoMSIA
COPD
CP
CRISPR
CS
CsA
CSF
CT
CTA
CTD
CYP(450)
CYP3A4
DCE-MRI
DDI

xi

Biliary excretion index
Brain like endothelial cell
Blood Retinal Barrier
Bile salt export pump (gene ABCB11)
human colon adenocarcinoma cell line
Constitutive androstane receptor (NR1I3)
Cholecystokinin-8
5-(and-6)-carboxy-2 0 ,7 0 -dichloro-fluorescein
Cystic fibrosis transmembrane conductance regulator
Committee for Medicinal Products for Human Use
Chinese hamster ovary (cell line)
Conditionally immortalized proximal tubule epithelial cells
Clash-detection guided iterative search with rotamer
relaxation
Clearance
Apical efflux clearance
Biliary clearance
Diffusional clearance
Active basolateral efflux clearance
Diffusional clearance in (i) or out (o) of the membrane
Intrinsic clearance
Passive clearance
Renal clearance
Active uptake clearance
Maximum observed blood concentration of drug
Substrate media concentration
Central nervous system
Concentrative nucleoside transporters (SLC28A subfamily)
Copy number variation
Concurrent medication
Canalicular membrane vesicles
Comparative molecular analysis
Comparative molecular similarity indices analysis
Chronic obstructive pulmonary disease
Choroid Plexus
Cluster regularly interspaced short palindromic repeats
Candidate selection
Cyclosporine A
Cerebrospinal fluid
Computed tomography
Clinical trial application
Common technical document
Cytochrome P450
Cytochrome P450 3A4
Dynamic contrast-enhanced magnetic resonance imaging
Drug–drug interaction

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xii

DIA
DILI
DME
DMPK
DNA
DRM
ECM
EMA
ENT
E17bG
ER
ESC
E1S
EGTA
ENT
F
Fa
Fg
FAH
FBS
FaSSIF
FeSSIF
(US) FDA
fa
fm
ft
FTIH
fu
fub
FXR
GFJ
GFR
GI tract/GIT
GLUT
GMO
GR
GSH
GST
HEK293
HIV
HGNC
HMG-CoA
HNF4a

Abbreviations

data independent acquisition
Drug induced liver injury
Drug metabolizing enzyme
Drug metabolism and pharmacokinetics
Deoxyribonucleic acid
Drug related material
Extracellular matrix
European Medicines Agency
Equilibrative nucleoside transporter (subfamily SLC29A)
Estradiol-17b-glucuronide
Endoplasmic reticulum
Embryonic stem cell
Estrone-1-sulfate
ethylene glycol tetraacetic acid
Equilibrative nucleoside transporter (SLC29A subfamily)
Bioavailability
Fraction of the dose that is absorbed from the intestinal
lumen to the intestinal enterocytes
Fraction of the dose that escapes pre-systemic intestinal
first pass elimination
Fumarylacetoacetate hydrolase
Foetal bovine serum
Fasted state simulated intestinal fluid
Fed state simulated intestinal fluid
(United States) Food and Drugs Administration
Fraction of dose absorbed
Fraction metabolized
Fraction transported
First time in human
Fraction unbound
Fraction unbound in blood
Farnesoid X receptor (NR1H4)
Grape fruit juice
Glomerular filtration rate
Gastro-intestinal tract
Glucose transporter
Genetically modified organism
glucocorticoid receptor (NR3C1)
Glutathione (reduced state)
Glutathione S-transferase enzyme
Human embryonic kidney cells
Human immunodeficiency virus
Human Genome Organisation Gene Nomenclature
Committee
3-Hydroxy-3-methyl-glutaryl-Coenzyme A reductase
Hepatic nuclear factor 4alpha (NR2A1)

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Abbreviations

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HUGO
I
IC50
ID
IHC
Iin.max
IND
iPSC
IR
ISF
ITC
IVIVC
IVIVE
Jmax
ka
Kd
Ki
Km(app)
Kp
LAT
LC-MS/MS
LD
LLC-PK1
logP
LOID
LTC4
LXR
m/z
MA
MALDI
MATE
MATE1
MATE2
MCT
MDCK
MDCK II
MDR
MDR1
MHLW
MMP
MPPþ

xiii

Human Genome Organisation
Inhibitor concentration
The concentration of inhibitor required to inhibit transport
by 50%
injected dose
Immunohistochemistry
Maximum inhibitor concentration at the inlet to the liver
Investigational new drug
Induced pluripotent stem cell
Immediate release
brain interstitial fluid
International Transporter Consortium
In vitro–in vivo correlation
In vitro–in vivo extrapolation
Maximum number of APIs translocated across area per time
by a given transporter
Absorption rate constant of the inhibitor
dissociation constant
Inhibitory constant
Michaelis constant in Michaelis–Menten kinetics
(apparent)
Partition coefficient
L-type amino acid transporter
Liquid chromatography tandem mass spectrometry
Lethal dose
Lilly Laboratories Culture-Pig Kidney Type 1 (cell line)
logarithm of the partition coefficient, a measure of
lipophilicity
Lead optimization and identification
Leukotriene C4
Liver X receptor (NR1H3)
Mass to charge ratio
Marketing authorization
Matrix assisted laser desorption ionization
Multidrug and toxin extrusion protein
Multidrug and toxin extrusion protein (gene SLC47A1)
Multidrug and toxin extrusion protein (gene SLC47A2)
Monocarboxylic acid transporter
Madin Darby canine kidney (cell line)
Madin Darby canine kidney, type II (cell line)
Multidrug resistance protein
Multidrug resistance protein 1 (also known as P-gp, gene
ABCB1)
Ministry of Health, Labour and Welfare
Matrix metalloproteinases
1-methyl-4-phenylpyridinium

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xiv

MQAPs
mRNA
MRI
MRP
MRP2
MRP4
MW
NaDC3
NAT
NBD
NCE
NDA
NIR
NME
NMR
NPT4
NR
NSAID
NSF
NT
NTBC
NTCP
NumHBA
NumHBD
OAT
OAT1
OAT3
OATP
OATP1A2
OATP1B1
OATP1B3
OATP2B1
OCT
OCT1
OCT2
OCTN
OCTN1
OCTN2
OSTa/b
Papp
PAMPA
PBEC
PBPK
Pcar
PCR

Abbreviations

Model quality assessment programmes
Messenger riboxynucleic acid
Magnetic resonance imaging
Multidrug resistance associated protein
Multidrug resistance associated protein 2 (gene ABCC2)
Multidrug resistance associated protein 4 (gene ABCC4)
Molecular weight
Sodium dependent dicarboxylate transporter 3 (SLC13A3)
N-acetyltransferase
Nucleotide binding domain
New chemical entity
New drug application
Near infrared imaging
New molecular entity
Nuclear magnetic resonance
Sodium phosphate transporter 4
Nuclear receptor
Non-steroidal anti-inflammatory drug
Nephrogenic systemic fibrosis
Nutrient transporter
2-(2-nitro-4-fluoro-methylbenzoyl)-1,3-cyclohexanedione
Na-taurocholate co-transporting polypeptide
Number of hydrogen bond acceptors
Number of hydrogen bond donors
Organic anion transporter
Organic anion transporter 1 (gene SLC22A6)
Organic anion transporter 3 (gene SLC22A8)
Organic anion transporting polypeptide
Organic anion transporting polypeptide 1A2
(gene SLCO1A2)
Organic anion transporting polypeptide 1B1 (gene SLCO1B1)
Organic anion transporting polypeptide 1B3 (gene SLCO1B3)
Organic anion transporting polypeptide 2B1 (gene SLCO2B1)
Organic cation transporter
Organic cation transporter (gene SLC22A1)
Organic cation transporter (gene SLC22A2)
Organic cation/carnitine transporter
Organic cation/carnitine transporter 1 (gene SLC22A4)
Organic cation/carnitine transporter 2 (gene SLC22A5)
Organic solute transporter a/b (gene SLC51A/B)
Apparent permeability studied in vitro
Parallel artificial membrane permeability assay
Porcine brain endothelial cell
Physiologically based pharmacokinetic
saturable carrier-mediated permeability
Polymerase chain reaction

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Abbreviations

PD
PDB
Pdiff
PDUFA
PDMS
PEff,man
PEPT
PEPT1
PEPT2
PET
P-gp
PK
PK/PD
PMDA
POC or PoC
Ppas
PPAR
PSbile
PSeff
PSinf
PXR
QH
QSAR
QWBA
R&D
RAF
rag
RBE
rBSEP
RCSB
REF
ROC
RPTEC
RT-PCR
RXR
SCH
SCHH
SCID
SERT
SF
SGLT
SLC
SLCO
SLC22
SLC47
SLCO1A2

xv

Pharmacodynamics
Protein Data Bank
passive diffusion
Prescription Drug User Fee Act
Polydimethylsiloxane
Effective permeability in humans studied in vivo
Peptide transporter
Peptide transporter 1 (gene SLC15A1)
Peptide transporter 2 (gene SLC15A2)
Positron emission tomography
P-glycoprotein (also known as MDR1, gene ABCB1)
Pharmacokinetics
Pharmacokinetics/pharmacodynamics
Pharmaceuticals and Medical Devices Agency (Japan)
Proof of concept
Passive diffusional driven permeability
Peroxisome proliferator activated receptor
Intrinsic biliary clearance
Intrinsic sinusoidal efflux clearance
Intrinsic uptake clearance
Pregnane X receptor (NR1I2)
Hepatic blood flow
Quantitative structure–activity relationship
Quantitative Whole Body Autoradiography
Research and development
relative activity factor
Recombinant activating gene
Rat brain endothelial
Rat bile salt export pump (gene ABCB11)
Research Collaboratory for Structural Bioinformatics
Relative expression factor
Receiver operating characteristics
Renal proximal tubule epithelial cells
Reverse transcriptase polymerase chain reaction
Retinoid X receptor
Sandwich-cultured hepatocytes
Sandwich-cultured human hepatocytes
Severe combined immunodeficiency
Serotonin transporter
Scaling factor
Sodium glucose linked transporter
Solute carrier gene superfamily
Solute carrier organic anion transporter gene subfamily
Solute carrier subfamily 22
Gene encoding MATE
Gene encoding OATP1A2

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