Pharmacokinetic Optimization in Drug Research
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Bernard Testa, Han van de Waterbeemd, Gerd Folkers, Richard Guy (Eds.)

Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical, and Computational Strategies




ISBN: 3-906390-22-5
668 pages
December 2001


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.


  1. Preface (B. Testa)


    1. Pharmacokinetic Challenges in Lead Optimization (G. Gaviraghi, R.J. Barnaby and M. Pellegatti)

    2. Modelling in Preclinical and Clinical Drug Development (L.P. Balant and M. Gex-Fabry)


    1. 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)

    2. Relations of Molecular Properties with Drug Disposition: The Cases of Gastrointestinal Absorption and Brain Penetration (H. van de Waterbeemd and D.A. Smith)

    3. Structure-Metabolism Relations, and the Challenge of redicting Biotransformation (B. Testa and G. Cruciani)

    4. Concepts in Prodrug Design to Overcome Pharmacokinetic Problems (B. Testa and J.M. Mayer)


    1. Methodologies in Cell Culture (H. Wunderli-Allenspach)

    2. Biological Models to Assess Drug Bioavailability (R.T. Borchardt)

    3. Biological Models to Study Blood-Brain Barrier Permeation (S.D. Krämer, N.J. Abbott and D.J. Begley)

    4. Biological Models to Study Skin Permeation (N. Sekkat and R.H. Guy)

    5. Biopharmaceutical Aspects of Nasal and Pulmonary Drug Delivery (P. Colombo, D. Cocconi, P. Santi, R. Bettini, G. Massimo, P.L. Catellani and C. Terzano)

    6. Significance of Plasma Protein Binding in Drug Research (S. Urien, J.-P. Tillement and J. Barré)

    7. High-Throughput ADE Screening (O. Kretz and A. Probst)

    8. In Vitro Models for Early Studies of Drug Metabolism (J.H. Lin and A.D. Rodrigues)

    9. Addressing Toxicological Issues in the Lead Optimization Phase of Drug Discovery and Evelopment (P. Bentley)


    1. Physicochemical Parameters as Tools in Drug Discovery and Lead Optimization (B. Faller and F. Wohnsland)

    2. Lipophilicity profiles: theory and measurement (J. Comer and K. Tam)

    3. High-Throughput Measurements of Solubility Profiles (A. Avdeef)

    4. Cyclic voltammetry as a new tool to study the partitioning and proton transport behaviour of ionized drugs (F. Reymond, G. Bouchard and H. Girault)

    5. Biolipid pKas and the Lipophilicity of Ampholytes and Ion Pairs (R.A. Scherrer)
      Recent Advances in Reversed-Phase-HPLC Techniques to Determine Lipophilicity (C. Yamagami)

    6. Liposome /Water Partitioning: Theory, Techniques and Applications (S.D. Krämer)

    7. Importance of the Mobile Phase in Immobilized Artificial Membrane Chromatography (K.L. Hauer and C. Pidgeon)

    8. 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)

    9. NMR Spectroscopy for the Study of Drug-Phospholipid Interactions (R. Fruttero)


    1. Virtual Screening of Molecular Properties: A Comparison of Log P Calculators (M.E. Duban, M.G. Bures, J. DeLazzer and Y.C. Martin)

    2. Quantitative Structure-Absorption Relationships (H.van de Waterbeemd)

    3. Hydrogen Bonding, the Last Mystery in Drug Design? (H. Kubinyi)

    4. 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)

    5. VolSurf and its Interest in Structure-Disposition Relationships (G. Cruciani, S. Clementi, P. Crivori, P.-A. Carrupt and B. Testa)

    6. Molecular Modeling Approaches to Predict Metabolism and Toxicity (A.M. ter Laak and N.P.E. Vermeulen)


    1. Molecular Biology, Drug Design and Drug Delivery: Bringing It All Together (V.H.L. Lee, S.K. Wu and C. Chu)

    2. 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).