Drug Transporters: Volume 1: Role and Importance in ADME and Drug Development

494 Pages·2016·6.95 MB·English

by  Glynis Nicholls

Drug Transporters
Volume 1: Role and Importance in ADME and Drug Development
RSC Drug Discovery Series
Editor-in-chief
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: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
4: Accounts in Drug Discovery
5: New Frontiers in Chemical Biology
6: Animal Models for Neurodegenerative Disease
7: Neurodegeneration
8: G Protein-Coupled Receptors
9: Pharmaceutical Process Development
10: Extracellular and Intracellular Signaling
11: New Synthetic Technologies in Medicinal Chemistry
12: New Horizons in Predictive Toxicology
13: Drug Design Strategies: Quantitative Approaches
14: Neglected Diseases and Drug Discovery
15: Biomedical Imaging
16: Pharmaceutical Salts and Cocrystals
17: Polyamine Drug Discovery
18: Proteinases as Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques and Applications
21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials for Overcoming Biological Barriers
23: Physico-Chemical and Computational Approaches to Drug Discovery
24: Biomarkers for Traumatic Brain Injury
25: Drug Discovery from Natural Products
26: Anti-Inflammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules
28: Drug Discovery for Psychiatric Disorders
29: Organic Chemistry of Drug Degradation
30: Computational Approaches to Nuclear Receptors
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
How to obtain future titles on publication:
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Drug Transporters
Volume 1: Role and Importance in ADME
and Drug Development
Edited by
Glynis Nicholls
Independent Consultant, Wem, Shropshire, UK
Email: [email protected]
Kuresh Youdim
F. Hoffman-La Roche AG, Basel, Switzerland
Email: [email protected]
RSCDrugDiscoverySeriesNo.54
PrintISBN:978-1-78262-069-3
TwovolumesetprintISBN:978-1-78262-867-5
PDFeISBN:978-1-78262-379-3
EPUBeISBN:978-1-78262-868-2
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Preface
The original aim of this book was to produce a useable handbook on drug
transporters, one that would be in the offices and laboratories of scientists
from every discipline as a source of reference, be it on the fundamental
aspects, or some of the newer, emerging disciplines of transporter science.
To date, there are no books that specifically address this aspect, concen-
tratinginsteadonin-depthreviewsanddiscussionsofparticulartopics.We
hope that this book, divided into two volumes, will fill the current gap by
encompassing a review of the available knowledge, techniques and tools
within the transporter sciences as they relate to drug disposition and
pharmacokinetics. It brings together the collective knowledge of over 200
yearsofexpertisefromanetworkofscientistsfromavarietyofbackgrounds
and countries, with a particular focus being given to the role of membrane
transporters in drug absorption, distribution, metabolism and elimination
(ADME),andtheirimpactondrugsafetyanddrugefficacy.Sincethebookis
intendedforbothnewcomersandestablishedscientists,coverageisgivento
almostallareasofthefield,togetherwithlinkstodatabases,referencesand
reviews for the interested reader.
For ease of reference, the book as a whole is divided into four sections,
witheachsectiondescribingthecurrent(2016)situationinthefieldofdrug
transporters. Given the extensive nature of the topics chosen, and our wish
toincludeasmanysubjectareasaspossible,ithasbeennecessarytodivide
the book into two separate volumes, with the first volume concentrating
primarily on the theory and practice of those drug transporters currently
used within the pharmaceutical industry and the second volume outlining
someoftheemergingareaswithinthefield.However,itisintendedthatthe
two volumes should, where possible, be retained together for reference
purposesandouruseoftheterm‘book’willgenerallyrefertobothvolumes.
Inthefirstvolume,DrugTransporters:Volume1RoleandImportanceinADME
RSCDrugDiscoverySeriesNo.54
DrugTransporters:Volume1:RoleandImportanceinADMEandDrugDevelopment
EditedbyGlynisNichollsandKureshYoudim
rTheRoyalSocietyofChemistry2016
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
vii
viii Preface
and Drug Development, some of the basic concepts are introduced in the
initialchapter,withsubsequentchaptersfocusingonthekey ADME organs
(liver, gastrointestinal tract, kidney, blood–brain barrier and lung) and how
thedifferentialexpressionofamultitudeofcharacterizeddrugtransporters
can impact the fate of both endogenous and exogenous compounds within
the human body. The following two sections cover preclinical models (in
silico, in vitro and in vivo), and modelling approaches used within the
pharmaceuticalindustryandhowthesecanbevaluabletoolsindetermining
the importance and clinical impact of transporter mediated drug–drug
interactions.Thecurrentregulatoryguidanceisalsodiscussedinthecontext
of transporters and their potential clinical impact. The second volume
Drug Transporters: Volume 2: Recent Advances and Emerging Technologies, is
dedicated to ourfinal section onemerging transporterscience, introducing
some of the newer areas and technologies where research is ongoing but is
notnecessarilypartofroutineinvestigations.Topicsrangefromfactorsthat
may impact transporter form and function (regulation of expression,
enzyme–transporter interplay and pharmacogenomics) through to more
practicalapproachestoimproveourunderstandingoftransporter–mediated
interactions (using microfluidics, proteomics, in vivo imaging and
bioinformatics/cheminformatics). Transporters in other organs and tissues
ofthebody,notcoveredinDrugTransporters:Volume1:RoleandImportance
in ADME and Drug Development, are also briefly discussed. This section
servestoillustratenotonlyhowthetransporterfieldisprogressinginmany
different areas, but also how our knowledge is still incomplete, with much
still to be done.
Incompletingouroriginalaim,itwasclearthatabooksuchasthiscould
only be achieved through collaboration—from the initialideas and support
of the Royal Society of Chemistry and the Drug Metabolism Discussion
Group (DMDG), through to the cooperation and efforts of a total of 61
authors who are experts in their fields, drawn from industry, academia,
commercial laboratories and regulatory authorities in Europe, the USA and
Asia. The involvement and continued commitment to this book from all of
ourcollaboratorswasoutstanding,especiallygiventheirongoingworkloads,
and we remain indebted to them. Mention should also be made of our
steering team of scientists, for their invaluable input into formulating the
overall book outline, and to our panel of external reviewers, whose input
helpedtoensurethatthescientificcontentofthebookwasaccurateandup
to date.
Given the many months dedicated to this work by such an extensive
network of expert scientists, we sincerely hope that this translates into a
book that will be used by many people in the coming years as a valuable
source of reference.
Glynis Nicholls
Kuresh Youdim
Acknowledgements
The editors would like to thank the following people for their input into
reviewing the chapters of both volumes of this book:
Drug Transporters: Volume 1: Role and Importance in ADME and Drug
Development
Members of the steering team and DMDG: Dr Peter Kilford (DMDG
Committee/Covance Ltd), Dr Mohammed Ullah (Roche), John Keogh (JPK
Consulting), Dr Pradeep Sharma (AstraZeneca), Dr Silke Simon (Roche),
Susan Cole (MHRA) and Dr Mohammed Atari (Cyprotex), for their helpful
input and independent review of several chapters.
Prof. Bruno Hagenbuch (University of Kansas) and Dr Bruno Stieger
(University Hospital, Zurich) for their review of Chapter 7.
Dr Michael Gertz (Roche) for his review of Chapter 9.
Dr Agn`es Poirier (Roche) for her review of Chapter 10.
Dr Terry Shepard and Dr DavidWright (MHRA), and Dr Eva GilBerglund
(MPA) for their review of Chapter 11.
Drug Transporters: Volume 2: Recent Advances and Emerging Technologies
Prof. Per Artursson and Dr Fabienne Gaugaz (Uppsala University) for their
review of Chapter 3.
DrP¨arNordellandDrConstanzeHilgendorf(AstraZeneca)fortheirreview
of Chapter 4.
Dr Jose Ulloa (Bioxydyn Ltd) for his review of Chapter 6.
Dr Marco Berrera (Roche) for his review of Chapter 7.
RSCDrugDiscoverySeriesNo.54
DrugTransporters:Volume1:RoleandImportanceinADMEandDrugDevelopment
EditedbyGlynisNichollsandKureshYoudim
rTheRoyalSocietyofChemistry2016
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
ix