The blood-brain barrier and drug delivery to the CNS

261 Pages·2000·8.52 MB·English

by  D J Begley

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IN THE TED STATES OF AME
m
~jnSg C ollege London
L~ndon, ~ngland
~ j n Cgol~leg e London
London, ~ngland
MARCEL
MARCELD EKKERIN, C. NEWY ORK BASEL
0
DEKKER
Now that the search for and developmenotf new drugs are increasinglyb ased
on models relating function to structure, it is becoming apparent that in the
case of drugs acting on the central nervous system (CNS), such models are also
crucial for the mechanisms determining uptake into the brain, This realization
implies better understandingof the relationshipo f transport at the blood-brain
barrier to drug structure and physicochemical properties. Within this volume
we have included a number of chapters describing crucial current areas of
investigation relevant to CNS drug penetration. These include mathematical
and computer models to predict drug entry and distribution in the brain on
the basiso f molecular descriptors and the usoef various in vitro modelso f the
blood-brain barrier, composed of cultured endothelial cells, to further predict
transport of drugs and solutes.
The potential of microdialysis in studying the kineticso f drug entry into
the CNS and in determining the true brain interstitial fluid concentration of
drugs is explored. Three chapters deawl ith specific transporters for drugs into
and out of the brain, with special emphasis on the rapidly expanding area of
multidrug transporters and their role in restricting CNS penetration of drugs.
Other chapters examine the metabolism of drugs within the brain and the
mechanisms of activation and detoxification of pharmacological agents; the
targeting of large molecules, including proteins and peptides; and the new
technique of introducing drugs conjugated with nanoparticle suspensions.F i-
nally, the possibilitieso f using imaging techniques to record drug kinetics and
binding in the living human subject are introduced.
iii
This volume will prove invaluable to researchers interested in the funda-
mental function of the blood-brain barrier and to those in the pharmaceutical
industry interested in rational drug design directed at targeting drugs to the
brain.
This book arose from a symposium with the same tihteleld, in Frankfurt
am Main, Germany. The symposium was organized by the editors during a
period when Michael Bradbury and David Begley jointly held the Friedrich
Merz Visiting Professorship at the Institute of Pharmaceutical Technology,
University of Frankfurt. This Chair is endowed by the Merz Pharmaceutical
Company and the authors are grateful to the company and Dr. Jochen Huck-
man, who gave much support to the symposium and to us during our stay in
Germany. Thanks are also due to Johann Wolfgang Goethe-Universitat and
to Professor Kreuter’s Institute for hosting the sy~pos~uamnd making our
time in Frankfurt a happy and productive occasion.
In the interests of fully comprehensive coverage of the current field we
have invited a few additional scientists of international stature to contribute.
We thank the contributors for their time and effort in producing this book.
David J. Begley
~ichaeWl . ~ r a d b u ~
Jiirg Kreuter
...
Preface 111
Contrib~tors vii
1. History and Physiology of the Blood-Brain Barrier in
Relation to Delivery of Drugs to the Brain
~ichaeWl . B r a d b ~ ~
2. Physicoche~icalF actors that Influence Brain Uptake
~ i ~ h aHe.lA braham and James A. Platts
3. The Development of In Vitro Models for the Blood-Brain
Barriers Blood-CSF and 33
Christiane ~ngelbertD~o,r othea Korte, hors ten Nitz,
~ e l ~Furantk e, ~ a t t ~ i a s ~ a sJoea~ch~ima W~ehge,n er,
and ~ans-~oachiCmal la
4. In Vitro Models of the Blood-Brain Barrier and Their Use
Development Drug in 65
R. Cecchelli, B. Dehouck, L. Descamps, L. Fenart, V. Buie-
Scherrer, C. hem, G. Torpier, and M. P. De~o~ck
vi ~ont~nts
5. The Application of Microdialysis Techniques to the Study of
Drug Transport Across the Blood-Brain Barrier 77
A. G. de Boer, ~lizabethC . M. de hnge, Inez C. J. van der
Sandt, and Douwe D. Breimer
6. The Role of Brain Extracellular Fluid Production and Efflux
Mechanisms in Drug Transport to the Brain 93
David J. Begley, Anthony Regina, Fran~oi~R~ouex t Ehsan
~llahK han, Christopher Rollinson, and Joan Abbott
7. The Relevance of P-Glycoprotein in Drug Transport to the
Brain: The Use of Knockout Mice as a Model System 109
Ulrich Mayer
8. Specific Mechanis~sfo r Transporting Drugs Into Brain 121
Akira Tsuji
9. Drug Meta~olisin~ t he Brain: Benefits and Risks 145
Alain Minn, Ramon D. S. ~l-BachC~la, ire Bayol-Deniz~tt
Philippe Lagrange, Fun~ilayoG . Suleman, and Daniela
Gradinaru
10. Targeting Macromolecules to the Central Nervous System 171
Ulrich Bickel
11. Using Nanoparticles to Target Drugs to the Central Nervous
System 205
Jiirg Kreuter and Renad N. Alyautdin
12. Basic CNS Drug Transport and Binding Kinetics In Vivo 225
Albert Gjedde, Antony D. Gee, and Donald ~rederickS mith
Index 243
oan Abbott Division of Physiology, King’s College London, London, En-
gland
.
A b r a ~ aD~e partment of Chemistry, University College Lon-
don, London, England
in Department of Pharmacology, I. M. Sechenov Mos-
cow Medical Academy, Moscow, Russia
enizot Dhpar~ementd e PharmacologieU, niversitkH enri
Poincarh-Nancy 1, CNRS, ando oeuvre-1~s-Nancy, France
egley Division of Physiology, King’s College London, London,
England
ickel Department of P~armaceuticaSl ciences, School of Pharmacy,
Texas Tech ~niversi~Aym, arillo, Texas
r a ~ D~ivi~sion~ of yPhy siology,K ing’sC ollegeL ondon,
London, England
rei~er Division of Phar~aco~ogLye, iden/Amsterdam Center
for Drug Research, University of Leiden, Leiden, The Netherlands
vi i