Pharmacokinetics and Metabolism in Drug Design 2nd Revised edition [Hardback]

Preface		ix
Abbreviations and Symbols		xiii
Physicochemistry		1	(18)
Physicochemistry and Pharmacokinetics		1	(1)
Partition and Distribution Coefficient as Measures of Lipophilicity		2	(3)
Limitations on the Use of 1-Octanol		5	(1)
Further Understanding of Log P		6	(4)
Unravelling the Principal Contributions to Log P		6	(1)
Hydrogen Bonding		6	(2)
Molecular Size and Shape		8	(2)
Alternative Lipophilicity Scales		10	(1)
Different Solvent Systems		10	(1)
Chromatographic Approaches		10	(1)
Liposome Partitioning		10	(1)
Computational Approaches to Lipophilicity		11	(1)
Membrane Systems to Study Drug Behaviour		12	(1)
Dissolution and Solubility		13	(2)
Why Measure Solubility?		13	(1)
Calculated Solubility		14	(1)
Ionisation (pKa)		15	(4)
Pharmacokinetics		19	(20)
Setting the Scene		19	(1)
Intravenous Administration: Volume of Distribution		19	(1)
Intravenous Administration: Clearance		20	(2)
Intravenous Administration: Clearance and Half-life		22	(1)
Intravenous Administration: Infusion		23	(2)
Oral Administration		25	(1)
Repeated Doses		26	(2)
Development of the Unbound (Free) Drug Model		28	(1)
Unbound Drug and Drug Action		28	(3)
Unbound Drug Model and Barriers to Equilibrium		31	(2)
Slow Offset Compounds		33	(2)
Factors Governing Unbound Drug Concentration		35	(4)
Absorption		39	(16)
The Absorption Process		39	(1)
Dissolution		40	(2)
Membrane Transfer		42	(4)
Barriers to Membrane Transfer		46	(3)
Models for Absorption Estimation		49	(2)
Estimation of Absorption Potential		51	(1)
Computational Approaches		51	(4)
Distribution		55	(12)
Membrane Transfer Access to the Target		55	(1)
Brain Penetration		56	(3)
Volume of Distribution and Duration		59	(5)
Distribution and Tmax		64	(3)
Clearance		67	(16)
The Clearance Processes		67	(1)
Role of Transport Proteins in Drug Clearance		68	(2)
Interplay Between Metabolic and Renal Clearance		70	(1)
Role of Lipophilicity in Drug Clearance		71	(12)
Renal Clearance		83	(8)
Kidney Anatomy and Function		83	(1)
Lipophilicity and Reabsorption by the Kidney		84	(1)
Effect of Charge on Renal Clearance		85	(1)
Plasma Protein Binding and Renal Clearance		85	(2)
Balancing Renal Clearance and Absorption		87	(1)
Renal Clearance and Drug Design		88	(3)
Metabolic (Hepatic) Clearance		91	(30)
Function of Metabolism (Biotransformation)		91	(1)
Cytochrome P450		92	(12)
Catalytic Selectivity of CYP2D6		94	(3)
Catalytic Selectivity of CYP2C9		97	(1)
Catalytic Selectivity of CYP3A4		98	(6)
Other Oxidative Metabolism Processes		104	(3)
Oxidative Metabolism and Drug Design		107	(2)
Non-Specific Esterases		109	(2)
Function of Esterases		109	(1)
Ester Drugs as Intravenous and Topical Agents		110	(1)
Prodrugs to Aid Membrane Transfer		111	(1)
Enzymes Catalysing Drug Conjugation		112	(4)
Glucuronyl and Sulpho-Transferases		112	(3)
Methyl Transferases		115	(1)
Glutathione S-Transferases		115	(1)
Stability to Conjugation Processes		116	(1)
Pharmacodynamics and Conjugation		117	(4)
Toxicity		121	(32)
Toxicity Findings		121	(5)
Pharmacophore-induced Toxicity		121	(2)
Structure-Related Toxicity		123	(2)
Metabolism-induced Toxicity		125	(1)
Importance of Dose Size		126	(1)
Epoxides		126	(2)
Quinone Imines		128	(5)
Nitrenium Ions		133	(1)
Iminium Ions		134	(2)
Hydroxylamines		136	(1)
Thiophene Rings		137	(2)
Thioureas		139	(1)
Chloroquinolines		139	(1)
Stratification of Toxicity		140	(1)
Toxicity Prediction: Computational Toxicology		141	(1)
Toxicogenomics		141	(1)
Enzyme Induction (CYP3A4) and Drug Design		142	(4)
Enzyme Inhibition and Drug Design		146	(7)
Inter-Species Scaling		153	(12)
Objectives of Inter-Species Scaling		153	(1)
Allometric Scaling		153	(4)
Volume of Distribution		154	(2)
Clearance		156	(1)
Species Scaling: Adjusting for Maximum Life Span Potential		157	(1)
Species Scaling: Incorporating Differences in Metabolic Clearance		158	(1)
Inter-Species Scaling for Clearance by Hepatic Uptake		159	(2)
Elimination Half-Life		161	(1)
Scaling to Pharmacological Effect		161	(2)
Single Animal Scaling		163	(2)
High(er) Throughput ADME Studies		165	(14)
The High-Throughput Screening (HTS) Trend		165	(1)
Drug Metabolism and Discovery Screening Sequences		165	(2)
Physicochemistry		167	(2)
Solubility		168	(1)
Lipophilicity		168	(1)
Absorption/Permeability		169	(1)
Pharmacokinetics		169	(1)
Metabolism and Inhibition		170	(1)
The Concept of ADME Space		171	(2)
Computational Approaches in PK and Metabolism		173	(2)
QSPR and QSMR		173	(1)
PK Predictions Using QSAR and Neural Networks		173	(1)
Is In Silico Meeting Medicinal Chemistry Needs in ADME Prediction?		174	(1)
Physiologically-Based Pharmacokinetic (PBPK) Modelling		175	(1)
Outlook		175	(4)
Index		179

Dennis Smith has worked in the pharmaceutical industry for the past 30 years since gaining his Ph.D. from the University of Manchester. For the last 18 years he has been at Pfizer global research and Development, Sandwich where he is vice President-Pharmacokinetics, Dynamics and Metabolism. His research interests and publications span all aspects of Drug Discovery and Development particularly where drug metabolism knowledge can impact on the design of more efficacious and safer drugs. During this 30-year span he has helped in the Discovery and Development of eight marketed NCEs, with hopefully several more to come. He has authored over 100 publications. He is active in a teaching role holding appointments as visiting Professor at the University of Liverpool and Honorary Senior Lecturer at the University of Aberdeen and lectures widely to students at several other Universities. His wish in much of his work is "to inspire another generation to take up the cudgel against disease". Han van de Waterbeemd studied physical organic chemistry at the Technical University of Eindhoven and did a Ph.D. in medicinal chemistry at the University of Leiden, The Netherlands. After a post-doc with Bernard Testa at the University of Lausanne, Switzerland, he became a faculty member for 5 years and taught medicinal chemistry to pharmacy students at the universities of Berne and Basel, Switzerland. In his pharmaceutical career he worked for Roche, Pfizer and Astra-Zeneca where he is now global project leader of their platform for in silico predictions of ADME/Tax properties. He published more than 133 peer reviewed papers and book chapters, and (co-) edited 11 books. His research interests include the role of physicochemical and structural molecular properties in drug disposition and in silico modeling of ADMET properties. Don Walker has a degree in Biochemistry from the University of London and spent four years assisting research involving the biochemistry of inborn errors of metabolism. He joined the Drug Metabolism Department at Pfizer in Sandwich in 1986 and since then has contributed to the drug metabolism and pharmacokinetic evaluations on several drug discovery and development projects including amlodopine, dofetilide, sildenafil, variconazole and maraviroc. He has published numerous papers on drug metabolism and pharmacokinetics and during his career at Pfizer he has been an active contributor to the UK Drug Metabolism Discussion Group, at various times having served as committee member, chairman and course tutor.