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Description
(Short description)
A concise introduction to the parameters and processes governing the absorption, distribution and retention of drug compounds in the body, now covering also modern approaches of ADME screening and evaluation.
(Text)
An understanding of pharmacokinetics is necessary to ensure that drugs that are active in vitro will also be active in the human body. The optimization of the pharmacokinetic properties of lead compounds is therefore of central importance to drug development. This concise introduction to the world of ADME and drug toxicity discusses the significant parameters and processes important for the absorption, distribution and retention of drug compounds in the body, plus the potential problems created by their transformation into toxic byproducts. The authors, all employed at Pfizer in the discovery and development of new active substances, cover everything from the fundamental principles right up to the latest developments using high throughput methods to analyze the pharmacokinetic properties of active substances. Particular emphasis is placed on the impact of pharmacokinetic parameters on the discovery of new drugs - one of the most challenging tasks in global pharmaceutical research.
(Table of content)
PHYSICOCHEMISTRY
Partition and Distribution Coefficient as Measures of Lipophilicity
Limitations on the Use of Octanol
Further Understanding of log P
Alternative Lipophilicity Scales
Computational Approaches to Lipophilicity
Membrane Systems to Study Drug Behaviour
NEW: Dissolution and Solubility
NEW: Ionisation (pKa)
PHARMACOKINETICS
Intravenous Administration: Volume of Distribution
Intravenous Administration: Clearance
Clearance and Half-Life
Intravenous administration: Infusion
Oral Administration
Repeated Doses
Development of the Unbound (Free) Drug Model
Unbound Drug and Drug Action
Unbound Drug Model and Barriers to Equilibrium
Slow Offset Compounds
Factors Governing Unbound Drug Concentration
ABSORPTION
The Absorption Process
Dissolution
Membrane Transfer
Barriers to Membrane Transfer
Models for Absorption Estimation
Estimation of Absorption Potential
Computational Approaches
DISTRIBUTION
Membrane Transfer Access to the Target
Brain penetration
Volume of Distribution and Duration
Distribution and Tmax
CLEARANCE
The Clearance Processes
Role of Transport Proteins in Drug Clearance
Interplay Between Metabolic and Renal Clearance
Role of Lipophilicity in Drug Clearance
RENAL CLEARANCE
Kidney Anatomy and Function
Lipophilicity and Reabsorption by the Kidney
Effect of Charge on Renal Clearance
Plasma Protein Binding and Renal Clearance
Balancing Renal Clearance and Absorption
Renal Clearance and Drug Design
METABOLIC (HEPATIC) CLEARANCE
Function of Metabolism (Biotransformation)
Cytochrome P450
Other oxidative processes
Oxidative Metablism and Drug Design
Non-Specific Esterases
Prodrugs to Aid Membrane Transfer
Enzymes Catalysing Drug Conjugation
Stability to Conjugation Processes
Pharmacodynamics and Conjugation
TOXICITY
Toxicity Findings
Importance of dose size
Toxicity of selected compound classes
Stratification of Toxicity
Toxicity Prediction - Computational Toxicology
Toxicogenomics
Enzyme Induction (CYP3A4) and Drug Design
Enzyme Inhibition and Drug Design
INTERSPECIES SCALING
Objectives of Allometric Scaling
Allometric Scaling
Species Scaling: Adjusting for Maximum Life-Span Potential
Species Scaling: Incorporating Differences in Metabolic Clearance
Inter-Species Scaling for Clearance by Hepatic Uptake
Elimination Half-Life
NEW: Scaling to pharmacological effect
NEW: Single animal scaling
HIGH(ER) THROUGHPUT ADME STUDIES
The HTS Trend
Drug Metabolism and Discovery Screening Sequences
Physicochemistry
Absorption / Permeability
Pharmacokinetics
NEW: Metabolism and Inhibition
NEW: The concept of ADME space
Computational Approaches in PK and Metabolism Prediction
Outlook
