Drug Disposition and Pharmacokinetics From Principles to Applications

Transcription

1 Drug Disposition and Pharmacokinetics From Principles to Applications Stephen H. Curry Professor of Pharmacology and Physiology, University of Rochester, USA Robin Whelpton Senior Lecturer, Queen Mary University of London, UK

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3 Drug Disposition and Pharmacokinetics From Principles to Applications

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5 Drug Disposition and Pharmacokinetics From Principles to Applications Stephen H. Curry Professor of Pharmacology and Physiology, University of Rochester, USA Robin Whelpton Senior Lecturer, Queen Mary University of London, UK

6 This edition first published 2011 Ó 2011 John Wiley & Sons, Ltd. Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Library of Congress Cataloging-in-Publication Data Curry, Stephen H. Drug disposition and pharmacokinetics : from principles to applications / Stephen H. Curry and Robin Whelpton. p. ; cm. Includes bibliographical references and index. ISBN (cloth) 1. Pharmacokinetics. 2. Biopharmaceutics. 3. Drugs Metabolism. I. Whelpton, Robin. II. Title. [DNLM: 1. Pharmacokinetics. 2. Biopharmaceutics. 3. Pharmaceutical Preparations metabolism. QV 38 C976da 2010] RM301.5.C dc A catalogue record for this book is available from the British Library. Print ISBN: epdf ISBN obook ISBN: Set in 10/12pt, Times-Roman by Thomson Digital, Noida, India

7 Contents Preface About the Authors xvii xxi 1 Chemical Introduction: Sources, Classification and Chemical Properties of Drugs Introduction Source of drugs Drug nomenclature and classification Properties of molecules Decomposition of drugs Hydrolysis Oxidation Photodecomposition Racemization Physicochemical interactions between drugs and other chemicals Chemical bonding and interactions between molecules Solubility Law of mass action Reversible reactions and equilibrium constants Sequential reactions Reaction order and molecularity Decay curves and half-lives First-order decay Zero-order decay Second-order decay Ionization Henderson Hasselbalch equation Partition coefficients Effect of ionization on partitioning Stereochemistry Cis-trans isomerism Optical isomerism Absolute configuration Importance of stereochemistry in pharmacology 21 Further reading and references 22 2 Drug Administration and Distribution Introduction Drug transfer across biological membranes Passive diffusion ph-partition hypothesis Drug administration 26

8 vi Contents Oral administration Presystemic metabolism P-Glycoprotein Gastrointestinal motility and splanchnic blood flow Food and drugs Sublingual administration Rectal administration Intravenous and intra-arterial injections Intramuscular and subcutaneous injections Transdermal application Insufflation Inhalation Other routes of administration Drug distribution Extent of distribution Apparent volume of distribution Mechanisms of sequestration ph differences Binding to macromolecules Dissolution in lipids Active transport Special processes Kinetics of distribution Tissue distribution of thiopental Tissue distribution of guanethidine Tissue distribution: more modern approaches Microdialysis Autoradiography Positron emission tomography (PET) Plasma protein binding Assessing protein binding Equilibrium dialysis Ultrafiltration Molecular aspects of protein binding Microcalorimetry Fluorescence spectroscopy Circular dichroism (CD) Electron paramagnetic resonance spectroscopy (EPR) Commentary Pharmacological importance of binding to plasma proteins Summary 50 References and further reading 50 3 Drug Elimination Introduction Metabolism Phase 1 metabolism Cytochrome P450 superfamily Other oxidases Hydrolysis Reductions Examples of phase 1 oxidation 59

9 Contents vii Oxidation of alcohols Aliphatic and aromatic hydroxylations Oxidative desalkylation N- and S-oxidation Oxidative deamination Desulfuration Combination of reactions Miscellaneous reactions Phase 2 metabolism D-Glucuronidation Sulfation N-Acetylation Methylation Glycine conjugates Conjugation with glutathione Kinetics of metabolism Excretion Urine Glomerular filtration Active tubular secretion Passive diffusion Renal clearance Effect of urine ph and flow rate Biliary excretion Expired air Saliva Stomach and intestine Breast milk Other routes of excretion Sweat Hair and nails Genital secretions Cycling processes Enterohepatic cycling Significance of cyclic processes 76 References and further reading 76 4 Elementary Pharmacokinetics Introduction Single-compartment models Systemic clearance Why drugs have different elimination half-lives Intravenous administration Half-life Area under the curve Absorption Area under the curve Special cases: k a < l and k a ¼ l Special case: lag time Infusions Zero-order input Loading dose 89

10 viii Contents Multiple doses Non-linear kinetics Phenytoin Ethanol Relationship between dose, onset and duration of effect Limitations of single-compartment models Summary 97 References and further reading 97 5 More Complex and Model Independent Pharmacokinetic Models Introduction Multiple compartment models Intravenous injections Concentrations in the peripheral compartment Microconstants Apparent volumes of distribution Clearance Absorption Infusions Multiple oral dosing Concept of compartments Relationship between dose and duration of effect Curve fitting and choice of most appropriate model Graphical solution: method of residuals Iterative curve-fitting Weighted-regression Choice of model Quality of the data Model independent approaches Calculation of V Area and clearance Statistical moment theory Estimating AUMC Example of application of SMT Population pharmacokinetics Summary 118 References and Further Reading Kinetics of Metabolism and Excretion Introduction Metabolite kinetics Basic concepts Fraction of metabolite formed More complex situations Active metabolites Effect of presystemic metabolism Interconversion of drug and metabolite Renal excretion Kinetics of urinary excretion Renal clearance Effect of urine flow rate Specific drug examples 132

11 Contents ix Amphetamine Ethanol Fluphenazine Excretion in faeces 134 References and further reading Further Consideration of Clearance, and Physiological Modelling Introduction Clearance in vitro (metabolic stability) Microsomes Hepatocytes Clearance in vivo Apparent oral clearance Two-compartment models Systemic clearance at steady-state Additivity of clearance Hepatic intrinsic clearance Effect of plasma protein binding on elimination kinetics Influence of protein binding on hepatic clearance Influence of protein binding and volume of distribution on half-life First-pass metabolism In vitro to in vivo extrapolation Limiting values of clearance Safe and effective use of clearance Physiological modelling Practical considerations Inhomogeneity of plasma 153 References and further reading Drug Formulation: Bioavailability, Bioequivalence and Controlled-Release Preparations Introduction Dissolution Systemic availability Effect of bioavailability on plasma concentration time curves Formulation factors affecting bioavailability Origins of variation Diluents Granulating and binding agents Lubricants and surfactants Disintegrating agents Miscellaneous Coated tablets Capsules Examples of drugs showing bioavailability variations Bioequivalence Controlled-release preparations Conclusions 167 References and further reading Factors Affecting Plasma Concentrations Introduction 169

12 x Contents 9.2 Time of administration of dose Time of day, and association of dosing with meal times Food, diet and nutrition Physical interaction with food Macronutrients Micronutrients Smoking Circadian rhythms Absorption The liver The kidney Intravenous and other injected doses Pharmacodynamics Weight and obesity General principles Obesity Sex Absorption and bioavailability Distribution Metabolism Excretion Effects Pregnancy Physiological and biochemical changes Hormonal effects Transporters The foetus Ambulation, posture and exercise The gastrointestinal tract Transdermal absorption Tissue distribution Subcutaneous and intramuscular injections The liver The kidneys Body temperature 184 References and Further reading Pharmacogenetics and Pharmacogenomics Introduction Terminology Methods for the study of pharmacogenetics Studies in twins Phenotyping and genotyping N-Acetyltransferase Isoniazid Sulfonamides Other drugs Plasma cholinesterase Suxamethonium Cytochrome P450 polymorphisms Cytochrome 2D Cytochrome 2C9 193

13 Contents xi Cytochrome 2C Cytochromes 3A4/ Other cytochrome P450 polymorphisms Alcohol dehydrogenase and acetaldehyde dehydrogenase Thiopurine methyltransferase Phase 2 enzymes UDP-glucuronosyltransferases Sulfotransferases Glutathione transferases Transporters Pharmacodynamic differences 198 References and Further Reading Developmental Pharmacology and Age-related Phenomena Introduction Scientific and regulatory environment in regard to younger and older patients Terminology Physiological and pharmacokinetic processes Absorption Binding and tissue distribution The blood brain barrier Liver function Changes in CYP-450 isoforms during the life cycle Renal function Metabolic and pharmacodynamic phenomena Body surface area versus weight Age groups Neonates and children Elderly Further examples 211 Further reading and references Effects of Disease on Drug Disposition Introduction Gastrointestinal disorders and drug absorption General considerations Inflammatory conditions of the intestines and coeliac disease Congestive heart failure Altered intestinal function Altered liver blood flow Altered rate of metabolism aminopyrine Altered route of metabolism glyceryl trinitrate Altered clearance mexilitine Congestive heart failure plus renal problems toborinone Decompensated and treated CHF torasemide Oedema Liver disease Pathophysiology Liver blood flow, binding to plasma proteins, and intrinsic hepatic clearance 220

14 xii Contents Methods of investigation Examples Drug effects Renal impairment General considerations Mathematical approach Examples Thyroid disease General considerations Examples Summary 233 References and further reading Quantitative Pharmacological Relationships Introduction Concentration effect relationships (dose response curves) Antagonism Variation Some illustrations of dose response curves in vivo The importance of relating dose effect and time-action studies The fundamental single dose time-action relationship The fundamental multiple-dose concentration effect relationship 247 References and further reading Pharmacokinetic/Pharmacodynamic Modelling: Simultaneous Measurement of Concentrations and Effect Introduction PK/PD modelling Objectives Single-compartment, time-independent PK/PD models Time-dependent models Ebastine and carebastine Unequal distribution within plasma: ethanol and glutethimide Hysteresis Pharmacokinetic distribution models Thiopental and propofol Receptors in the peripheral compartment models LSD Digoxin Effect compartment models Warfarin type models Other examples 264 References and further reading Extrapolation from Animals to Human Beings and Translational Science Introduction Allometric scaling Refinements to allometric scaling 273

15 Contents xiii Effect of neoteny Pharmacokinetic time Practical aspects of allometry Dose-ranging versus microdosing studies Statistical approaches Translational science 277 References and further reading Peptides and Other Biological Molecules Introduction Chemical principles PEGylation Assay methods Pharmacokinetic processes Administration and dosage Bioequivalence Distribution Metabolism Excretion Plasma kinetics and pharmacodynamics Examples of particular interest Cholecystokinins Ciclosporin Heparin Trastuzumab Erythropoietin Vasopressin and desmopressin Conclusion 290 References and further reading Drug Interactions Introduction Terminology Time action considerations Interactions involving drug distribution and metabolism Enzyme induction Enzyme inhibition Plasma protein binding and tissue uptake Mechanisms of enzyme induction Extent of drug interactions Key examples Warfarin Cimetidine and ketoconazole Digoxin and quinidine Alcohol and other depressants (notably barbiturates) Further examples and mechanisms of a wide range of drug interactions When are drug interactions important? Desirable drug drug interactions 307