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MORE ABOUT THIS BOOK
Main description:
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.
Back cover:
Although parallel synthesis combined with high-throughput screening has made it easier to generate highly potent drug candidates, many of these compounds never make the grade because they either prove to be unsafe or lack the necessary physicochemical and pharmacokinetic properties. In Optimization in Drug Discovery: In Vitro Methods, a panel of researchers and experts from leading universities and major pharmaceutical companies from all over the world provide proven solutions to this expensive problem with a collection of cutting-edge experimental protocols for early in vitro evaluation of new chemical entities (NCE). These readily reproducible assays measure such critical parameters as physicochemical properties, adsorption, plasma binding, metabolism, drug interactions, and toxicity. All protocols follow the successful Methods in Molecular Biologyâ„¢ series format, each one offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.
Comprehensive and highly practical, Optimization in Drug Discovery: In Vitro Methods systematically collects and describes the key methods for uncovering-as early in the discovery stage as possible-those defects that can eliminate candidate drugs from preclinical and clinical development.
Contents:
pKa, Solubility and Lipophilicity: Assessing Physicochemical Properties of Lead Compounds
Yushen Guo and Hong Shen
Use of Caco-2 Cell Monolayers to Study Drug Absorption and Metabolism
Ming Hu, Jie Ling, Huimin Lin, and Jun Chen
Absorption Screening Using the PAMPA Approach
Jeffrey A. Ruell and Alex Avdeef
In Situ Single-Pass Perfused Rat Intestinal Model for Absorption and Metabolism
Eun Ju Jeong, Yan Liu, Huimin Lin, and Ming Hu
In Vitro Permeation Study With Bovine Brain Microvessel Endothelial Cells
Seong-Hee Park, Sung-Hack Lee, Yaming Su, and Patrick J. Sinko
An Enzymatic Microplate Assay for Testing P-Glycoprotein Substrates and Inhibitors
S. Orlowski, J. Nugier, and Eric Ezan
Evaluation of Drug-Transporter Interactions Using In Vitro Cell Models
Yaming Su and Patrick J. Sinko
Plasma Protein-Binding Methods in Drug Discovery
Lucinda H. Cohen
Isothermal Titration Calorimetry Characterization of Drug-Binding Energetics to Blood Proteins
Gary W. Caldwell and Zhengyin Yan
Metabolic Stability Assessed by Liver Microsomes and Hepatocytes
David C. Ackley, Kevin T. Rockich, and Timothy R. Baker
In Vitro Drug Metabolite Profiling Using Hepatic S9 and Human Liver Microsomes
Wu-Nan Wu and Linda A. McKown
In Vitro Identification of UDP-glucuronosyltransferases Involved in Drug Metabolism
Michael H. Court
In Vitro CYP Induction in Human Hepatocytes
Daniel R. Mudra and Andrew Parkinson
High-Throughput Screening of Human Cytochrome P450 Inhibitors Using Fluorometric Substrates: Methodology for 25 Enzyme/Substrate Pairs
David M. Stresser
Evaluation of Cytochrome P450 Inhibition in Human Liver Microsomes
Zhengyin Yan and Gary W. Caldwell
Identification of CYP Mechanism-Based Inhibitors
Amin A. Nomeir, Jairam Palamanda, and Leonard Favreau
Detection of DNA Adducts by 32P-Postlabeling Analysis
Naomi Suzuki, Padmaja M. Prabhu, and Shinya Shibutani
Covalent DNA Adduct Formation Mediated by Cytochrome P450
Marie StiborovĂ¡
Application of In Vitro Comet Assay for Genotoxicity Testing
Bojana Zegura and Metka Filipic
Assessing DNA Damage Using a Reporter Gene System
Xuming Jia and Wei Xiao
Improvement of the Ames Test Using Human Liver S9 Preparation
Atsushi Hakura, Satoshi Suzuki, and Tetsuo Satoh
Screening for Chemical Mutagens Using the Mouse Lymphoma Assay
Tao Chen and Martha M. Moore
A High-Throughput Binding Assay for HERG
Keith Finlayson and John Sharkey
In Vitro Drug Metabolism: Thiol Conjugation
Wei Tang and Randy R. Miller
In Vitro Screening Assay of the Reactivity of Acyl Glucuronides
Sébastien Bolze
Index
PRODUCT DETAILS
Publisher: Springer (Humana Press)
Publication date: October, 2010
Pages: 434
Weight: 637g
Availability: POD
Subcategories: Pharmacology
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CUSTOMER REVIEWS
"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