The science and applied approaches of enzyme inhibition in drug discovery and developmentOffering a unique approach that includes both the pharmacologic and pharmaco-kinetic aspects of enzyme inhibition, Enzyme Inhibition in Drug Discovery and Development examines the scientific concepts and experimental approaches related to enzyme inhibition as applied in drug discovery and drug development.With chapters written by over fifty leading experts in their fields, Enzyme Inhibition in Drug Discovery and Development fosters a cross-fertilization of pharmacology, drug metabolism, pharmacokinetics, and toxicology by understanding the "good" inhibitions—desirable pharmacological effects—and "bad" inhibitions—drug–drug interactions and toxicity. The book discusses:The drug discovery process, including drug discovery strategy, medicinal chemistry, analytical chemistry, drug metabolism, pharmacokinetics, and safety biomarker assessmentThe manipulations of drug metabolizing enzymes and transporters as well as the negative consequences, such as drug–drug interactionsThe inhibition of several major drug target pathways, such as the GPCR pathway, the NFkB pathway, and the ion channel pathwayThrough this focused, single-source reference on the fundamentals of drug discovery and development, researchers in drug metabolism and pharmacokinetics (DMPK) will learn and appreciate target biology in drug discovery; discovery biologists and medicinal chemists will also broaden their understanding of DMPK.
Author(s): Chuang Lu, Albert P. Li
Edition: 1
Year: 2010
Language: English
Pages: 876
ENZYME INHIBITION IN DRUG DISCOVERY AND DEVELOPMENT......Page 4
CONTENTS......Page 8
PREFACE......Page 12
CONTRIBUTORS......Page 14
PART I. DRUG DISCOVERY APPROACHES AND TECHNOLOGIES......Page 18
1. The Drug Discovery Process......Page 20
2. Medicinal Chemistry of the Optimization of Enzyme Inhibitors......Page 32
3. Bioanalytical Technologies in Drug Discovery......Page 60
4. Safety Biomarkers in Drug Development: Emerging Trends and Implications......Page 88
5. The Role of Drug Metabolism in Drug Discovery......Page 108
6. Applied Pharmacokinetics in Drug Discovery and Development......Page 194
PART II. INHIBITION OF THE DRUG METABOLIZING ENZYMES—THE UNDESIRABLE INHIBITION......Page 258
7. Enzyme Inhibition and Inactivation: Cytochrome P450 Enzymes......Page 260
8. Cytochrome P450 Induction......Page 282
9. Inhibition of Drug-Metabolizing Enzymes in the Gastrointestinal Tract and Its Influence on the Drug–Drug Interaction Prediction......Page 332
10. Enzyme Inhibition in Various In Vitro Systems......Page 362
11. Cytochrome P450 Degradation and Its Clinical Relevance......Page 380
12. Complexities of Working with UDP-Glucuronosyltransferases (UGTs): Focus on Enzyme Inhibition......Page 424
13. Evaluation of Inhibitors of Drug Metabolism in Human Hepatocytes......Page 440
14. Grapefruit Juice and Its Constituents as New Esterase Inhibitors......Page 460
15. Transporter–Xenobiotic Interactions: An Important Aspect of Drug Development Studies......Page 484
16. Polymorphisms of Drug Transporters and Their Clinical Implications......Page 520
17. Clinical Drug Interactions Due to Metabolic Inhibition: Prediction, Assessment, and Interpretation......Page 550
18. Predicting Interindividual Variability of Metabolic Drug–Drug Interactions: Identifying the Causes and Accounting for Them Using a Systems Approach......Page 566
PART III. INHIBITION OF THE DRUG TARGET ENZYMES—THE DESIRABLE INHIBITION......Page 586
19. NF-κB: Mechanism, Tumor Biology, and Inhibitors......Page 588
20. G-Protein-Coupled Receptors as Drug Targets......Page 642
21. Pharmacological Modulation of Ion Channels for the Treatment of Chronic Pain......Page 686
22. Targeting the mTOR Pathway for Tumor Therapeutics......Page 736
23. HIV-1 Protease Inhibitors as Antiretroviral Agents......Page 766
INDEX......Page 828
