Han van de Waterbeemd, Gerd Folkers, Richard Guy (Eds.)
Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical,
and Computational Strategies
In this age of combinatorial chemistry and high-throughput
technologies, bioactive compounds called hits are discovered by the thousands.
However, the road that leads from hits to lead compounds and then to
pharmacokinetically optimized clinical and drug candidates is very long indeed.
As a result, the screening, design, and optimization of pharmacokinetic
properties has become the bottleneck and a major challenge in drug research. To
shorten the time-consuming develop-ment and high rate of attrition of active
compounds ultimately doomed by hidden pharmacokinetic defects, drug researchers
are coming to incorporate structure-permeation, structure-distribution,
structure-metabolism, and structure-toxicity relations into drug-design
strategies. To this end, powerful biological, physicochemical, and computational
approaches are being developed whose objectives are to increase the clinical
relevance of drug design, and to eliminate as soon as possible compounds with
unfavorable physicochemical properties and pharmacokinetic profiles.
Toxicological issues are also of utmost importance in this paradigm.
There was, hence, an urgent need for a book covering this field in an
authoritative, didactic, comprehensive, factual, and conceptual manner. In this
work of unique breadth and depth, international authorities and practicing
experts from academia and industry present the most modern biological,
physicochemical, and computational strategies to optimize gastrointestinal
absorption, protein binding and distribution, brain permeation, and metabolic
profile. The biological strategies emphasized in the book include cell cultures
and high-throughput screens. The physicochemical strategies focus on the
determination and interpretation of solubility, lipophilicity, and related
molecular properties as factors and predictors of pharmacokinetic bahavior.
Particular attention is paid to the lipophilicity profiles of ionized compounds,
to lipophilicity measurements in anisotropic media (liposomes/water, IAM
columns), and to permeability across artificial membranes. Computational
strategies comprise virtual screening, molecular modelling, lipophilicity, and
H-bonding fields and their importance for structure-disposition relations.
This book is both about theoretical and technological breakthroughs. Thus,
molecular properties are contemplated from a dual perspective, namely a) their
interpretation in biological and/or physicochemical terms, and b) their value in
screening, lead optimization, and drug-candidate selection.
In addition to its 33 chapters, the book includes a CD-ROM containing the
invited lectures, oral communications and posters (in full version) presented at
the Second LogP Symposium, 'Lipophilicity in Drug Disposition -- Practical and
Computational Approaches to Molecular Properties Related to Drug Permeation,
Disposition and Metabolism', held at the University of Lausanne in March 2000.
Preface (B. Testa)
SETTING THE SCENE
Pharmacokinetic Challenges in Lead Optimization (G.
Gaviraghi, R.J. Barnaby and M. Pellegatti)
Modelling in Preclinical and Clinical Drug Development
(L.P. Balant and M. Gex-Fabry)
MOLECULAR AND BIOLOGICAL BACKGROUND
Structure of Liposomal Membranes in Relation to
Permeation (O.G. Mouritsen, H.K. Andersen, J.S. Andersen, J. Davidsen, L.K.
Nielsen and K. Jørgensen)
Relations of Molecular Properties with Drug
Disposition: The Cases of Gastrointestinal Absorption and Brain Penetration
(H. van de Waterbeemd and D.A. Smith)
Structure-Metabolism Relations, and the Challenge of
redicting Biotransformation (B. Testa and G. Cruciani)
Concepts in Prodrug Design to Overcome Pharmacokinetic
Problems (B. Testa and J.M. Mayer)
Methodologies in Cell Culture (H. Wunderli-Allenspach)
Biological Models to Assess Drug Bioavailability (R.T.
Biological Models to Study Blood-Brain Barrier
Permeation (S.D. Krämer, N.J. Abbott and D.J. Begley)
Biological Models to Study Skin Permeation (N. Sekkat
and R.H. Guy)
Biopharmaceutical Aspects of Nasal and Pulmonary Drug
Delivery (P. Colombo, D. Cocconi, P. Santi, R. Bettini, G. Massimo, P.L.
Catellani and C. Terzano)
Significance of Plasma Protein Binding in Drug Research
(S. Urien, J.-P. Tillement and J. Barré)
High-Throughput ADE Screening (O. Kretz and A. Probst)
In Vitro Models for Early Studies of Drug Metabolism
(J.H. Lin and A.D. Rodrigues)
Addressing Toxicological Issues in the Lead
Optimization Phase of Drug Discovery and Evelopment (P. Bentley)
Physicochemical Parameters as Tools in Drug Discovery
and Lead Optimization (B. Faller and F. Wohnsland)
Lipophilicity profiles: theory and measurement (J.
Comer and K. Tam)
High-Throughput Measurements of Solubility Profiles (A.
Cyclic voltammetry as a new tool to study the
partitioning and proton transport behaviour of ionized drugs (F. Reymond, G.
Bouchard and H. Girault)
Biolipid pKas and the Lipophilicity of Ampholytes and
Ion Pairs (R.A. Scherrer)
Recent Advances in Reversed-Phase-HPLC Techniques to Determine Lipophilicity
Liposome /Water Partitioning: Theory, Techniques and
Applications (S.D. Krämer)
Importance of the Mobile Phase in Immobilized
Artificial Membrane Chromatography (K.L. Hauer and C. Pidgeon)
High-Throughput Artificial Membrane Permeability
Studies In Early Lead Discovery and Development (M. Kansy, H. Fischer, K.
Kratzat, F. Senner, B. Wagner and I. Parrilla)
NMR Spectroscopy for the Study of Drug-Phospholipid
Interactions (R. Fruttero)
Virtual Screening of Molecular Properties: A Comparison
of Log P Calculators (M.E. Duban, M.G. Bures, J. DeLazzer and Y.C. Martin)
Quantitative Structure-Absorption Relationships (H.van
Hydrogen Bonding, the Last Mystery in Drug Design? (H.
Molecular Hydrogen-Bonding Potentials (MHBPs) in
Structure-Permeation Relations (G. Caron, S. Rey, G. Ermondi, P. Crivori, P.
Gaillard, P.-A. Carrupt and B. Testa)
VolSurf and its Interest in Structure-Disposition
Relationships (G. Cruciani, S. Clementi, P. Crivori, P.-A. Carrupt and B.
Molecular Modeling Approaches to Predict Metabolism and
Toxicity (A.M. ter Laak and N.P.E. Vermeulen)
Molecular Biology, Drug Design and Drug Delivery:
Bringing It All Together (V.H.L. Lee, S.K. Wu and C. Chu)
Pharmacokinetic lead optimization: fine art vs. blind
technology (B. Testa)
"This valuable book is presented in 6 sections (plus a
substantial index) .... provides a book of timely and unique, breadth and
depth". (Chemistry & Industry, 4 February 2002)
"...This book is a 'must have' ...." (Biomedial
Chromatgraphy, January 2003)
"Insgesamt bietet das Werk sehr viele interessante
Einblicke, so dass der "Testa" hoffentlich trotz seines hohen Preises weite
Verbreitung finden wird."
(BioTec 2002, 13(5-6).