Part 3 of the Handbook of Experimental Pharmacology (Concepts in Biochem­ ical Pharmacology) applies the principles enunciated in Parts 1 and 2 to clinical pharmacology and toxicology. The major objective is to elucidate the many factors that determine the relationships between pharmacokinetic aspects of the disposition and metabolism of drugs and their therapeutic or toxic actions in man. Because of the more restricted information obtainable in human studies, this volume reflects the editors' bias that an understanding of pharmacokinetics is fundamental for assessing pharmacologic or toxicologic effects of drugs in humans. The first chapter is a unique primer on when to apply and how to use pharmaco­ kinetic tools in human pharmacology. The second chapter explains the general assumptions underlying pharmacokinetic approaches both in simple terms for the novice and in mathematical form for the more sophisticated reader. Several chapters on determinants of drug concentration and activity discuss drug absorption, drug latentiation, drugs acting through metabolites, entero­ hepatic drug circulation, influence of route of drug administration on response, genetic variations in drug disposition and response, age differences in absorption, distribution and excretion of drugs, and pathologic and physiologic factors affecting absorption, distribution and excretion of drugs and drug response. The focus of these chapters is data obtained in human, rather than animal, studies. Most of the chapters contain new material never summarized previously.

Inhalt

Section Six: Determinants of Drug Concentration and Activity.- 59: Pharmacokinetics.- I. Introduction.- II. Absorption and Elimination; Linear, One-Compartment Systems.- A. Elimination of Single Intravenous Doses.- B. Apparent Volume of Distribution.- C. Urinary Excretion of Drug and Metabolites.- D. Drug Metabolite Levels in the Body.- E. Bioavailability and Absorption Kinetics.- F. Intravenous Infusions.- G. Repetitive Drug Administration.- III. Absorption, Distribution, and Elimination; Linear, Multicompartment Systems.- A. Distribution and Elimination of Single Intravenous Doses.- B. Apparent Volume of Distribution.- C. The Meaning of ?.- D. Bioavailability and Absorption Kinetics.- E. Intravenous Infusion.- F. Repetitive Drug Administration.- G. The "First-Pass" Effect.- H. Other Multicompartment Models.- IV. Pharmacokinetics of Non-Linear Systems.- A. Elimination of Single Intravenous Doses.- B. Various Processes Resulting in Non-Linear Elimination Kinetics.- C. Non-Linear Absorption Kinetics.- D. Repetitive Drug Administration.- V. Kinetics of Reversible Pharmacologic Effects.- A. One-Compartment Systems.- B. Multicompartment Systems.- VI. Some Useful Suggestions for the Experimentalist.- References.- 60: Other Aspects of Pharmacokinetics.- I. Introduction.- II. Factors that Affect the Rate of Distribution of Drugs in Tissues.- A. Permeability of Capillaries and Cells.- B. Lipid Solubility and Ionization of Drugs.- C. Differences in pH between Cells and Blood.- D. Reversible Binding of Drugs to Proteins and Other Components.- 1. General Considerations.- 2. Dissociation Rate Constants and Transit Times.- 3. Diffusion into Extracellular Spaces.- 4. Effect of Reversible Binding on the Clearance of Drugs by Liver.- E. Diffusion Barriers in the Extracellular Space.- F. Active Transport of Drugs.- G. Time-Delay Factors.- III. Some Problems in the Development of Pharmacokinetic Models for Tissues and Organs.- A. General Aspects.- B. Closed Model for a Tissue.- C. Perfusion Systems (Nonrecirculatory).- 1. General.- 2. Model 1.- 3. Model 2.- 4. Model 3.- 5. Model 4.- 6. Emptying of Tissue Compartments.- D. Pharmacokinetics of Drug Disposition and Metabolism after Intravenous Administration of Drugs.- 1. General.- 2. In vivo Kinetic Models.- a) Model I - Caternary 3-Pool System.- b) Model Ia fa Mammillary, Degenerate Diffusion Limited System).- c) Model II (a Mammillary, Caternary System).- d) Model III (2-Pool System).- e) Model IV (Mammillary, 3-Pool Flow-Limited System).- 3. General Comments on the Central Compartment.- 4. Concepts of Volume of Distribution.- a) Equations for Vd(eq), and Vd (?) in 2 and 3 Compartment Systems.- b) Volume of Distribution by the Extrapolation Method.- c) The Partition of Areas Method.- 5. Area under the Curve Method Applied to Metabolites.- 6. Effects of Reversible Binding of Drugs to Macromolecules on Pharmacokinetic Parameters.- a) General.- b) Effects of Reversible Binding on the Clearance of Drugs by a Single Organ.- c) Effects of Reversible Binding on the Volume of Distribution of Drugs.- d) Effects of Reversible Binding on Rate Constants of Elimination in Linear, First Order Models.- e) Non-Linear Binding.- f) Area Under the Curves (AUC) of Total Drug Concentration in Plasma.- Appendix 1.- References.- 61: Drug Latentiation.- I. Introduction.- II. Chemical and Structural Consideration.- III. Prodrug Design.- IV. Carboxylic Acid Drugs.- V. Alcohol Drugs.- VI. Amine Drugs.- References.- 62: Biotransformation of Drugs to Pharmacologically Active Metabolites.- I. Introduction.- II. Drugs Acting on the Central Nervous System.- A. Hypnotics and Sedatives.- a) Chloralhydrate.- B. Anticonvulsants.- a) Mephobarbital.- b) Primidone.- c) Trimethadione.- d) Methsuximide.- C. Centrally Acting Muscle Relaxant.- a) Zoxazolamine.- D. Narcotic Analgesics.- a) Codeine.- b) Meperidine.- c) Acetylmethadol.- d) Diphenoxylate.- E. Analgesic-Antipyretics, Anti-Inflammatory Agents, and Inhibitors of Uric Acid Synthesis.- a) Salicylates.- b) Phenacetin.- c) Aminopyrine.- d) Phenylbutazone.- e) Allopurinol.- f) (4-phenylthioethyl).- F. Drugs Used in the Treatment of Psychiatric Disorders.- 1. Drugs for Treatment of Psychoses.- a) Tetrabenazine.- 2. Drugs for Anxiety.- a) Chlordiazepoxide.- b) Diazepam.- c) Medazepam.- d) Prazepam.- 3. Psychotropic Drugs for Affective Disorders.- a) Tricyclic Compounds.- b) Monoaminoxidase (MAO) Inhibitors.- III. Drugs Acting at Synaptic and Neuroeffector Functional Sites.- A. Anticholinesterase Agents.- a) Parathion.- B. Drugs Acting on Postganglionic Adrenergic Nerve Endings and Structures Innervated by them (Sympathomimetic Drugs).- a) N-isopropylmethoxamine.- b) Fenfluramine.- c) Fenproporex.- C. Drugs Inhibiting Adrenergic Nerves and Structures Innervated by them.- 1. Adrenergic Neuron Blocking Agents.- a) ?-methyldopa.- b) ?-methyl-wt-tyrosine.- IV. Cardiovascular Drugs.- A. Antiarrhythmic Drugs.- a) Lidocaine.- b) Propranolol.- B. Vasodilator Drugs.- a) Diallylmelamine.- b) Prenylamine.- C. Drugs Lowering Blood Lipids or Glucose.- a) Nicotinic Acid.- b) Clofibrate.- c) 3,5-dimethylpyrazole.- d) 3,5-dimethylisoxazole.- e) Acetohexamide.- V. Chemotherapy of Parasitic Diseases.- A. Drugs Used in the Chemotherapy of Helminthiasis.- a) Lucanthone.- VI. Chemotherapy of Neoplastic Diseases.- A. Alkylating Agents.- a) Cyclophosphamide.- VII. Conclusions.- References.- 63: The Enterohepatic Circulation.- I. Introduction.- II. Methods for Studying the Enterohepatic Circulation.- III. The Enterohepatic Circulation of Bile Salts.- A. Excretion of Bile Salts.- B. Absorption of Bile Salts.- IV. Enterohepatic Circulation of Drugs.- A. Morphine.- B. Methadone.- C. Etorphine.- D. Digitoxin.- E. Diethylstilbestrol.- F. Steroids.- G. Indomethacin.- H. Glutethimide.- I. Amphetamine.- J. Butylated Hydroxytoluene.- K. Pentaerythritol Trinitrate.- L. Fenamates.- M. Phenothiazines.- N. Antibiotics.- V. Enhanced Biliary Excretion of Drugs.- A. Enhanced Biliary Plow.- B. Enhanced Formation of Metabolites.- C. Formation of Complexes.- References.- 64: Routes of Administration and Drug Response.- I. Introduction.- II. Enteral Administration of Drugs.- A. The Oral Route.- 1. Advantages of Oral Dosing.- 2. Disadvantages of Oral Dosing.- a) Slow Onset of Action.- b) Nonavailability of Oral Route.- c) Poor Drug Availability.- d) Selective Local Action.- B. Sublingual and Recta…