CiNii 図書 - Optimization in drug discovery : in vitro methods

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.

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 Stiborova 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 Sebastien Bolze Index

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Optimization in drug discovery : in vitro methods

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