P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come BASIC PHARMACOKINETICS AND PHARMACODYNAMICS P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come BASIC PHARMACOKINETICS AND PHARMACODYNAMICS An Integrated Textbook and Computer Simulations SARA ROSENBAUM A JOHN WILEY & SONS, INC., PUBLICATION P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come Copyright C⃝ 2011 by John Wiley & Sons, Inc. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada. 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For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data: Rosenbaum, Sara (Sara E.) Basic pharmacokinetics and pharmacodynamics : an integrated textbook and computer simulations / by Sara Rosenbaum. p. ; cm. Includes bibliographical references. ISBN 978-0-470-56906-1 (cloth) 1. Pharmacokinetics–Textbooks. 2. Pharmacokinetics–Computer simulation. 3. Drugs–Physiological effect–Textbooks. 4. Drugs–Physiological effect–Computer simulation. I. Title. [DNLM: 1. Pharmacokinetics. 2. Computer Simulation. 3. Pharmacological Phenomena. QV 38 RM301.5.R655 2011 615′.7–dc22 2010043288 Printed in Singapore eISBN: 9781118001059 10 9 8 7 6 5 4 3 2 1 P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come To S, M, and L P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come CONTENTS Preface xvii 1 Introduction to Pharmacokinetics and Pharmacodynamics 1 1.1 Introduction: Drugs and Doses, 1 1.2 Introduction to Pharmacodynamics, 3 1.2.1 Drug Effects at the Site of Action, 3 1.2.2 Agonists, Antagonists, and Concentration–Response Relationships, 6 1.3 Introduction to Pharmacokinetics, 9 1.3.1 Plasma Concentration of Drugs, 10 1.3.2 Processes in Pharmacokinetics, 11 1.4 Dose–Response Relationships, 13 1.5 Therapeutic Range, 14 1.5.1 Determination of the Therapeutic Range, 16 1.6 Summary, 18 2 Passage of Drugs Through Membranes 20 2.1 Introduction, 20 2.2 Structure and Properties of Membranes, 21 2.3 Passive Diffusion, 22 2.3.1 Transcellular Passive Diffusion, 24 2.3.2 Paracellular Passive Diffusion, 26 2.4 Carrier-Mediated Processes: Transport Proteins, 27 2.4.1 Uptake Transporters: SLC Superfamily, 28 2.4.2 Efflux Transporters: ABC Superfamily, 29 2.4.3 Characteristics of Transporter Systems, 31 vii P1: OTA/XYZ P2: ABC fm JWBS062-Rosenbaum February 16, 2011 7:24 Printer Name: Yet to Come viii CONTENTS 2.4.4 Simulation Exercise, 32 2.4.5 Clinical Examples of Transporter Involvement in Drug Response, 33 3 Drug Administration, Absorption, and Bioavailability 36 3.1 Introduction: Local and Systemic Drug Administration, 37 3.2 Common Routes of Systemic Drug Administration, 37 3.2.1 Intravascular Direct Systemic Administration, 37 3.2.2 Extravascular Parenteral Routes, 38 3.2.3 Other Extravascular Routes, 38 3.3 Overview of Oral Absorption, 40 3.4 Extent of Drug Absorption, 41 3.4.1 Bioavailability Factor, 41 3.4.2 Individual Bioavailability Factors, 42 3.5 Determinants of the Bioavailability Factor, 43 3.5.1 Disintegration, 43 3.5.2 Dissolution, 43 3.5.3 Formulation Excipients, 43 3.5.4 Adverse Events Within the Gastrointestinal Lumen, 44 3.5.5 Transcellular Passive Diffusion, 46 3.5.6 Paracellular Passive Diffusion, 47 3.5.7 Uptake and Efflux Transporters, 47 3.5.8 Presytemic Intestinal Metabolism or Extraction, 50 3.5.9 Presystemic Hepatic Metabolism or Extraction, 52 3.6 Factors Controlling the Rate of Drug Absorption, 53 3.6.1 Dissolution-Controlled Absorption, 54 3.6.2 Membrane Penetration–Controlled Absorption, 55 3.6.3 Overall Rate of Drug Absorption, 55 3.7 Biopharmaceutics Classification System, 55 Problems, 56 References, 57 4 Drug Distribution 60 4.1 Introduction, 61 4.2 Extent of Drug Distribution, 61 4.2.1 Distribution Volumes, 62 4.2.2 Tissue Binding and Plasma Protein Binding: Concentrating Effects, 64 4.2.3 Assessment of the Extent of Drug Distribution: Apparent Volume of Distribution, 65 4.2.4 Plasma Protein Binding, 72 4.3 Rate of Drug Distribution, 79 4.3.1 Perfusion-Controlled Drug Distribution, 80 4.3.2 Diffusion-Controlled Drug Distribution, 82 4.4 Distribution of Drugs to the Central Nervous System, 83 Problems, 86 References, 87