Optimization in Drug Discovery

1. Front Matter

   Pages i-xv

   PDF

2. pKa, Solubility, and Lipophilicity

   • Yushen Guo, Hong Shen

   Pages 1-17

3. Use of Caco-2 Cell Monolayers to Study Drug Absorption and Metabolism

   • Ming Hu, Jie Ling, Huimin Lin, Jun Chen

   Pages 19-35

4. Absorption Screening Using the PAMPA Approach

   • Jeffrey A. Ruell, Alex Avdeef

   Pages 37-64

5. In Situ Single-Pass Perfused Rat Intestinal Model for Absorption and Metabolism

   • Eun Ju Jeong, Yan Liu, Huimin Lin, Ming Hu

   Pages 65-76

6. In Vitro Permeation Study With Bovine Brain Microvessel Endothelial Cells

   • Seong-Hee Park, Sung-Hack Lee, Yaming Su, Patrick J. Sinko

   Pages 77-87

7. An Enzymatic Microplate Assay for Testing P-Glycoprotein Substrates and Inhibitors

   • S. Orlowski, J. Nugier, Eric Ezan

   Pages 89-102

8. Evaluation of Drug-Transporter Interactions Using In Vitro Cell Models

   • Yaming Su, Patrick J. Sinko

   Pages 103-110

9. Plasma Protein-Binding Methods in Drug Discovery

   • Lucinda H. Cohen

   Pages 111-122

10. Isothermal Titration Calorimetry Characterization of Drug-Binding Energetics to Blood Proteins

    • Gary W. Caldwell, Zhengyin Yan

    Pages 123-149

11. Metabolic Stability Assessed by Liver Microsomes and Hepatocytes

    • David C. Ackley, Kevin T. Rockich, Timothy R. Baker

    Pages 151-162

12. In Vitro Drug Metabolite Profiling Using Hepatic S9 and Human Liver Microsomes

    • Wu-Nan Wu, Linda A. McKown

    Pages 163-184

13. In Vitro Identification of UDP-Glucuronosyltransferases (UGTs) Involved in Drug Metabolism

    • Michael H. Court

    Pages 185-202

14. In Vitro CYP Induction in Human Hepatocytes

    • Daniel R. Mudra, Andrew Parkinson

    Pages 203-214

15. High-Throughput Screening of Human Cytochrome P450 Inhibitors Using Fluorometric Substrates

    • David M. Stresser

    Pages 215-230

16. Evaluation of Cytochrome P450 Inhibition in Human Liver Microsomes

    • Zhengyin Yan, Gary W. Caldwell

    Pages 231-244

17. Identification of CYP Mechanism-Based Inhibitors

    • Amin A. Nomeir, Jairam R. Palamanda, Leonard Favreau

    Pages 245-262

18. Detection of DNA Adducts by 32P-Postlabeling Analysis

    • Naomi Suzuki, Padmaja M. Prabhu, Shinya Shibutani

    Pages 263-278

19. Covalent DNA Adduct Formation Mediated by Cytochrome P450

    • Marie Stiborová

    Pages 279-299

20. Application of In Vitro Comet Assay for Genotoxicity Testing

    • Bojana Žegura, Metka Filipič

    Pages 301-313

Recent analyses of drug attrition rates reveal that a significant number of drug candidates fail in the later stage of clinical development owing to absorption, distribution, metabolism, elimination (ADME), and toxicity issues. Lead optimization in drug discovery, a process attempting to uncover and correct these defects of drug candidates, is highly beneficial in lowering the cost and time to develop therapeutic drugs by reducing drug candidate failures in development. At present, parallel synthesis combining with high-throughput screening has made it easier to generate highly potent compounds (i. e. , hits). However, to be a potential drug, a hit must have drug-like characteristics in addition to potency, which include optimal physicochemical properties, reasonable ph- macokinetic parameters, and good safety profiles. Therefore, research tools must be available in drug discovery to rapidly screen for compounds with favorable drug-like properties, and thus adequate resources can be directed to projects with high potential. Optimization in Drug Discovery: In Vitro Methods is a compilation of detailed experimental protocols necessary for setting up a variety of assays important in compound evaluation. A total of 25 chapters, contributed by many experts in their research areas, cover a wide spectrum of subjects including physicochemical properties, abso- tion, plasma binding, metabolism, drug interactions, and toxicity. A good pharmacokinetic profile has long been recognized as an imp- tant drug-like characteristic. Pharmacokinetic parameters are affected by many properties of drug molecules such as physicochemical nature, abso- tion, metabolic stability, and so on.

"This book covers most of the currently used techniques in lead optimization with respect to ADME and safety profiles. . .would be very useful addition to the library of any drug scientist interested in an introduction to these important methods. Each chapter treats its topic in a concise manner and provides ample references to lead the reader to more detailed information."-Doody's Health Sciences Book Review Journal

"...very useful technically...invaluable to those changing roles or joining a pharmaceutical company, it is also very helpful for scientists in the biotech industry who are new to drug discovery." - Immunology News

"The book provides a wealth of relevant information...the tome is neatly designed, well constructed and easy to read." - ISSX Newsletter

"...a useful reference handbook for in vitro ADMET assays." - ChemBioChem

• Johnson & Johnson Pharmaceutical Research & Development, Spring House

  Zhengyin Yan, Gary W. Caldwell

Policies and ethics