Dennis A. Smith, Han van de Waterbeemd,and Don K. Walker

Pharmacokinetics and Metabolism inDrug Design

Second Revised Edition

InnodataFile Attachment3527608281.jpg

Dennis A. Smith,

Han van de Waterbeemd,

and Don K. Walker

Pharmacokinetics and

Metabolism in Drug Design

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H.-D. H�ltje, H. Timmerman, J. Vacca, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Th. Dingermann, D. Steinhilber,G. Folkers (eds.)

Molecular Biology inMedicinal ChemistryVol. 21

2004, ISBN 3-527-30431-2

H. Kubinyi, G. M�ller (ed.)

Chemogenomics in DrugDiscoveryVol. 22

2004, ISBN 3-527-30987-X

T. I. Oprea (ed.)

Chemoinformatics in DrugDiscoveryVol. 23

2005, ISBN 3-527-30753-2

R. Seifert, T. Wieland (eds.)

G-Protein Coupled Receptorsas Drug TargetsVol. 24

2005, ISBN 3-527-30819-9

O. Kappe, A. Stadler

Microwaves in Organic andMedicinal ChemistryVol. 25

2005, ISBN 3-527-31210-2

W. Bannwarth, B. Hinzen (eds.)

Combinatorial ChemistryVol. 26, 2nd Ed.

2006, ISBN 3-527-30693-5

G. Cruciani (ed.)

Molecular Interaction FieldsVol. 27

2005, ISBN 3-527-31087-8

M. Hamacher, K. Marcus, K. St�hler,A. van Hall, B. Warscheid, H. E. Meyer(eds.)

Proteomics in Drug DesignVol. 28

2005, ISBN 3-527-31226-9

D. J. Triggle, M. Gopalakrishnan,D. Rampe, W. Zheng (eds.)

Voltage-Gated Ion Channelsas Drug TargetsVol. 29

2006, ISBN 3-527-31258-7

D. Rognan

Ligand Design for G Protein-coupled ReceptorsVol. 30

2006, ISBN 3-527-31284-6

Dennis A. Smith, Han van de Waterbeemd,and Don K. Walker

Pharmacokinetics and Metabolism inDrug Design

Second Revised Edition

Series Editors

Prof. Dr. Raimund MannholdMolecular Drug Research GroupHeinrich-Heine-Universit�tUniversit�tsstrasse 140225 D�sseldorfGermanyRaimund.mannhold@uni-duesseldorf.de

Prof. Dr. Hugo KubinyiDonnersbergstrasse 967256 Weisenheim am SandGermanykubinyi@t-online.de

Prof. Dr. Gerd FolkersCollegium HelveticumSTW/ETH Zentrum8092 Z�richSwitzerlandfolkers@collegium.ethz.ch

Authors

Dr. Dennis A. SmithPfizer Global Research and DevelopmentSandwich LaboratoriesDepartment of Drug MetabolismSandwich, Kent CT13 9NJUKdennis.a.smith@pfizer.com

Dr. Han van de WaterbeemdAstraZenecaAlderley Park, MacclesfieldCheshire SK10 4TGUKHan.VanDeWaterbeemd@astrazeneca.com

Dr. Don K. WalkerPfizer Global Research and DevelopmentSandwich LaboratoriesDepartment of Drug MetabolismSandwich, Kent CT13 9NJUKdon.walker@pfizer.com

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ISBN-13: 978-3-527-31368-6ISBN-10: 3-527-31368-0

V

Preface IX

Abbreviations and Symbols XIII

1 Physicochemistry 11.1 Physicochemistry and Pharmacokinetics 11.2 Partition and Distribution Coefficient as Measures of Lipophilicity 21.3 Limitations on the Use of 1-Octanol 51.4 Further Understanding of Log P 61.4.1 Unravelling the Principal Contributions to Log P 61.4.2 Hydrogen Bonding 61.4.3 Molecular Size and Shape 81.5 Alternative Lipophilicity Scales 101.5.1 Different Solvent Systems 101.5.2 Chromatographic Approaches 101.5.3 Liposome Partitioning 101.6 Computational Approaches to Lipophilicity 111.7 Membrane Systems to Study Drug Behaviour 121.8 Dissolution and Solubility 131.8.1 Why Measure Solubility? 131.8.2 Calculated Solubility 141.9 Ionisation (pKa) 15

2 Pharmacokinetics 192.1 Setting the Scene 192.2 Intravenous Administration: Volume of Distribution 192.3 Intravenous Administration: Clearance 202.4 Intravenous Administration: Clearance and Half-life 222.5 Intravenous Administration: Infusion 232.6 Oral Administration 252.7 Repeated Doses 262.8 Development of the Unbound (Free) Drug Model 282.9 Unbound Drug and Drug Action 28

Contents

VI

2.10 Unbound Drug Model and Barriers to Equilibrium 312.11 Slow Offset Compounds 332.12 Factors Governing Unbound Drug Concentration 35

3 Absorption 393.1 The Absorption Process 393.2 Dissolution 403.3 Membrane Transfer 423.4 Barriers to Membrane Transfer 463.5 Models for Absorption Estimation 493.6 Estimation of Absorption Potential 513.7 Computational Approaches 51

4 Distribution 554.1 Membrane Transfer Access to the Target 554.2 Brain Penetration 564.3 Volume of Distribution and Duration 594.4 Distribution and Tmax 64

5 Clearance 675.1 The Clearance Processes 675.2 Role of Transport Proteins in Drug Clearance 685.3 Interplay Between Metabolic and Renal Clearance 705.4 Role of Lipophilicity in Drug Clearance 71

6 Renal Clearance 836.1 Kidney Anatomy and Function 836.2 Lipophilicity and Reabsorption by the Kidney 846.3 Effect of Charge on Renal Clearance 856.4 Plasma Protein Binding and Renal Clearance 856.5 Balancing Renal Clearance and Absorption 876.6 Renal Clearance and Drug Design 88

7 Metabolic (Hepatic) Clearance 917.1 Function of Metabolism (Biotransformation) 917.2 Cytochrome P450 927.2.1 Catalytic Selectivity of CYP2D6 947.2.2 Catalytic Selectivity of CYP2C9 977.2.3 Catalytic Selectivity of CYP3A4 987.3 Other Oxidative Metabolism Processes 1047.4 Oxidative Metabolism and Drug Design 1077.5 Non-Specific Esterases 1097.5.1 Function of Esterases 1097.5.2 Ester Drugs as Intravenous and Topical Agents 1107.6 Prodrugs to Aid Membrane Transfer 111

Contents

VII

7.7 Enzymes Catalysing Drug Conjugation 1127.7.1 Glucuronyl and Sulpho-Transferases 1127.7.2 Methyl Transferases 1157.7.3 Glutathione S-Transferases 1157.8 Stability to Conjugation Processes 1167.9 Pharmacodynamics and Conjugation 117

8 Toxicity 1218.1 Toxicity Findings 1218.1.1 Pharmacophore-induced Toxicity 1218.1.2 Structure-related Toxicity 1238.1.3 Metabolism-induced Toxicity 1258.2 Importance of Dose Size 1268.3 Epoxides 1268.4 Quinone Imines 1288.5 Nitrenium Ions 1338.6 Iminium Ions 1348.7 Hydroxylamines 1368.8 Thiophene Rings 1378.9 Thioureas 1398.10 Chloroquinolines 1398.11 Stratification of Toxicity 1408.12 Toxicity Prediction: Computational Toxicology 1418.13 Toxicogenomics 1418.14 Enzyme Induction (CYP3A4) and Drug Design 1428.15 Enzyme Inhibition and Drug Design 146

9 Inter-Species Scaling 1539.1 Objectives of Inter-Species Scaling 1539.2 Allometric Scaling 1539.2.1 Volume of Distribution 1549.2.2 Clearance 1569.3 Species Scaling: Adjusting for Maximum Life Span Potential 1579.4 Species Scaling: Incorporating Differences in Metabolic

Clearance 1589.5 Inter-Species Scaling for Clearance by Hepatic Uptake 1599.6 Elimination Half-Life 1619.7 Scaling to Pharmacological Effect 1619.8 Single Animal Scaling 163

10 High(er) Throughput ADME Studies 16510.1 The High-Throughput Screening (HTS) Trend 16510.2 Drug Metabolism and Discovery Screening Sequences 16510.3 Physicochemistry 16710.3.1 Solubility 168

Contents

10.3.2 Lipophilicity 16810.4 Absorption/Permeability 16910.5 Pharmacokinetics 16910.6 Metabolism and Inhibition 17010.7 The Concept of ADME Space 17110.8 Computational Approaches in PK and Metabolism 17310.8.1 QSPR and QSMR 17310.8.2 PK Predictions Using QSAR and Neural Networks 17310.8.3 Is In SilicoMeeting Medicinal Chemistry Needs in ADME

Prediction? 17410.8.4 Physiologically-Based Pharmacokinetic (PBPK) Modelling 17510.9 Outlook 175

Index 179

ContentsVIII

IX

The concept of this book is simple. It represents the distillation of my experiencesover 25 years within drug discovery and drug development, and in particular howthe science of drug metabolism and pharmacokinetics impacts medicinal chemis-try. Hopefully it will be a source of some knowledge, but more importantly, a sti-mulus for medicinal chemists wanting to understand as much as possible aboutthe chemicals they make. As the work grew I realised it was impossible to fulfilthe concept of this book without involving others. I am extremely grateful to myco-authors Don Walker and Han van de Waterbeemd for helping turn a skeletoninto a fully clothed body, and in the process, contributing a large number of newideas and directions. Upon completion of the book I realise how little we knowand how much there is to do. Medicinal chemists often refer to the magic methyl.This term covers the small synthetic addition, which almost magically solves a dis-covery problem of transforming a mere ligand into a potential drug, beyond thescope of existing structure–activity relationships. A single methyl can disrupt crys-tal lattices, break hydration spheres, modulate metabolism, enhance chemical sta-bility, displace water in a binding site and turns the sometimes weary predicableplod of methyl, ethyl, propyl, futile into methyl, ethyl, another methyl magic! Thisbook has no magical secrets unfortunately, but time and time again the logicalsearch for solutions is eventually rewarded by unexpected gains.

January 2001, SandwichDennis A. Smith

A Personal Foreword to the First Edition

I took great personal satisfaction in seeing our thoughts turned into a book, andsat back to relax. Very soon as I glanced at the book I saw gaps, missing links,things I wish we had said better or included. Pride turned gradually to frustrationand provided the catalysis for a second edition. The experience spans 29 years, butmy wonder and admiration for the magic of medicinal chemistry and those thatpractice it remain undimmed.

July 2005 Dennis A. Smith

XI

A Personal Foreword to the Second Edition

XIII

Abbreviations and Symbols

Chapter 1

AbbreviationsCPC Centrifugal partition chromatographyCoMFA Comparative field analysis3D-QSAR Three-dimensional quantitative structure–activity relationshipsHDM Hexadecane membraneIUPAC International Union of Pure and Applied ChemistryMLP Molecular lipophilicity potentialRP-HPLC Reversed-phase high-performance liquid chromatographyPAMPA Parallel artificial membrane permeability assayPGDP Propylene glycol dipelargonatePSA Polar surface areaSF Shake flask, referring to traditional method to measure

log P or log DTPSA Topological polar surface area

SymbolsAPSUV Absorption potential measured in small unilamellar vesicles (SUV)Dlog D Difference between log D in octanol/water and log D in alkane/

waterDlog P Difference between log P in octanol/water and log P in alkane/

waterf Rekker or Leo/Hansch fragmental constant for log P contributionKa Ionisation constantK Polarity term, mainly related to hydrogen bonding capability of a

solutelog P Logarithm of the partition coefficient (P ) of neutral specieslog D Logarithm of the distribution coefficient (D) at a selected pH,

usually assumed to be measured in octanol/water

log Doct Logarithm of the distribution coefficient (D) at a selected pH,measured in octanol/water

log Dchex Logarithm of the distribution coefficient (D) at a selected pH,measured in cyclohexane/water

log D7.4 Logarithm of the distribution coefficient (D) at pH 7.4MW Molecular weightp Hansch constant; contribution of a substituent to log PpKa Negative logarithm of the ionisation constant Ka

Chapter 2

AbbreviationsADME Absorption, distribution, metabolism and excretionAUC Area under plasma concentration time curveCNS Central nervous systemCYP2D6 Cytochrome P450 2D6 enzymeGIT Gastrointestinal tractIV IntravenousPET Positive emission tomography

SymbolsAav Average amount of drug in the body over a dosing intervalAmax Maximum amount of drug in the body over a dosing intervalAmin Minimum amount of drug in the body over a dosing intervalCo Initial concentration after IV doseCavss Average plasma concentration at steady stateCp(f) Free (unbound) plasma concentrationCp(fo) Initial free (unbound) plasma concentrationCss Steady state concentrationCl ClearanceClu Unbound clearanceClH Hepatic clearanceCli Intrinsic clearanceCliu Intrinsic clearance of unbound drugClo Oral clearanceClp Plasma clearanceClR Renal clearanceClS Systemic clearanceD DoseE ExtractionEF Fractional responseEM Maximum responseF Fraction of dose reaching systemic circulation (bioavailability)Fda Fraction dose absorbed

Abbreviations and SymbolsXIV

fu Fraction of drug unboundKA Affinity constantKB Dissociation constant for a competitive antagonistKd Dissociation constantkel Elimination rate constantKm Affinity constant (concentration at 50% Vmax)ko Infusion ratek+1 Receptor on ratek–1 Receptor off rateL Ligandlog D7.4 Distribution coefficient (octanol/buffer) at pH 7.4ln 2 Natural logarithm of two (i.e. 0.693)pA2 Affinity of antagonist for a receptor (= –log10[KB])Q Blood flowR ReceptorRL Receptor ligand complexRO Receptor occupancys Substrate concentrationt Time after drug administrationT Dosing intervalt1/2 Elimination half-lifeVd Volume of distributionVd(f) Apparent volume of distribution of free (unbound) drugVmax Maximum rate of reaction (Michaelis–Menten enzyme kinetics)e Dosing interval in terms of half-life (= T / t1/2)

Chapter 3

AbbreviationsAUC Area under plasma concentration time curveCaco-2 Human colon adenocarcinoma cell line used as absorption modelGI GastrointestinalMDCK Madin–Darby canine kidney cell line used as absorption modelPSA Polar surface area

SymbolsA% Percentage of dose absorbed as measured in portal veinCLOGP MedChem/Biobyte log P estimation programF% Percentage of dose bioavailableFa Fraction absorbedFnon Fraction non-ionised at pH of 6.5IFV Intestinal fluid volume (250mL)ka Absorption rate constant in rats (min–1)log D Logarithm of distribution coefficient

XVChapter 3

Abbreviations and Symbols

log P Logarithm of partition coefficientlog S Logarithm of solubility in waterRT Average residence time in the small intestine (270min)S6.5 Solubility in phosphate buffer at pH of 6.5So Intrinsic solubility of the neutral species at 37 �CVL Volume of the lumenal contentsXo Dose administered

Chapter 4

AbbreviationsCNS Central nervous systemCSF Cerebrospinal fluid

SymbolsClp Plasma clearanceClu Unbound clearance of free drugDlog P Difference in log P values in octanol and cyclohexaneH-bond Hydrogen bondkel Elimination rate constantlog D7.4 Distribution coefficient at pH 7.4 (usually octanol/water)log P Partition coefficient (usually octanol)pKa Ionisation constantTmax Time to maximum observed plasma concentrationVd(f) Unbound volume of distribution of the free drug

Chapter 5

AbbreviationsATP Adenosine triphosphateBTL BilitranslocaseCYP450 Cytochrome P450MOAT Multiple organic acid transporterMRP Multi-drug resistance proteinNatp Sodium dependent acid transporter proteinOATP Organic acid transport proteinOCT1 Organic cation transporter 1OCT2 Organic cation transporter 2P-gp P-glycoproteinTxRA Thromboxane receptor antagonistTxSI Thromboxane synthase inhibitor

XVI

Chapter 8

SymbolsCl Clearancelog D7.4 Distribution coefficient (octanol/buffer) at pH 7.4t1/2 Elimination half-lifeVd Volume of distribution

Chapter 6

AbbreviationsGFR Glomerular filtration rate

SymbolsCp(f) Free (unbound) plasma concentrationlog D7.4 Logarithm of distribution coefficient (octanol/buffer) at pH 7.4

Chapter 7

AbbreviationsCOMT Catechol-O-methyl transferaseCYP Cytochrome P450CYP2D6 2D6 isoenzyme of the cytochrome P450 enzyme familyCYP2C9 2C9 isoenzyme of the cytochrome P450 enzyme familyCYP3A4 3A4 isoenzyme of the cytochrome P450 enzyme familyFMO Flavin mono-oxygenaseGST Glutathione S-transferaseMAO Monoamine oxidaseNEP Neutral endopeptidaseP450 Cytochrome P450PAPS 3¢-Phosphoadenosine-5-phosphosulfateUGT UDP-glucuronosyltransferases

Symbolslog D7.4 Logarithm of the octanol/water distribution coefficient at pH 7.4Km Affinity constant (concentration at 50% Vmax)

Chapter 8

AbbreviationsANF Atrial natriuretic factor (also ANP: atrial natriuretic peptide)COX CyclooxygenaseENCC Electroneutral Na-Cl cotransporterhFGF Human fibroblast growth factor

XVII

Abbreviations and Symbols

GSH GlutathioneHMG-CoA 3-Hydroxy-3-methylglutaryl coenzyme ALH Luteinizing hormone5-LPO 5-LipoxygenaseNK NeurokininNKCC Old name for ENCCPBPK/PD Physiologically-based pharmacokinetic/pharmacodynamic

(modelling)PCNA Proliferating cell nuclear antigenPPAR-c Peroxisome proliferator-activated receptor cTA2 ThromboxaneVEGF Vascular endothelial growth factor

Chapter 9

AbbreviationsBW Body weightCYP2C9 Cytochrome P450 2C9 enzymeGFR Glomerular filtration rateIV IntravenousMLP Maximum life span potentialP450 Cytochrome P450TxRAs Thromboxane receptor antagonists

SymbolsCmax Maximum plasma concentration observedCl ClearanceCli Intrinsic clearanceCliu Intrinsic clearance of unbound (free) drugClou Oral unbound clearance (i.e. oral clearance correct for free fraction)Cls Systemic clearancefb Fraction of plasma bound drugfu Fraction of drug unbound (to plasma proteins)fut Fraction of unbound drug in tissuesln Natural logarithmQ Organ blood flowR Ratio of binding proteins in extracellular fluid (except plasma) to

binding proteins in plasmar2 Correlation coefficientt1/2 Elimination half-lifeVd Volume of distributionVe Volume of extracellular fluidVp Volume of plasmaVr Volume of remaining fluid

XVIII

Chapter 10

Chapter 10

AbbreviationsADME Absorption, distribution, metabolism, excretionCYP3A4 Cytochrome P450 3A4DMPK Drug metabolism and pharmacokineticsHTS High-throughput screeningIAM Immobilised artificial membraneLC/MS Liquid chromatography/mass spectrometryMDR1 Gene coding for P-glycoprotein (P-gp); newer coding as ABCB1MTS Medium throughput screeningNADPH Nicotinamide adenine dinucleotide phosphateNMR Nuclear magnetic resonancePAMPA Parallel artificial membrane permeability assayPBPK Physiologically-based pharmacokineticsP-gp P-glycoproteinPK PharmacokineticsPK/PD Pharmacokinetics/pharmacodynamicsPSA Polar surface areaQSAR Quantitative structure–activity relationshipsSAR Structure–activity relationship7TMs Seven transmembrane loop receptorsUHTS Ultra-high-throughput screening

SymbolsDlog P Difference between octanol/water and alkane/water log P as a

measure for hydrogen bonding capacityKi Binding constant (to receptor or metabolising enzyme)log D7.4 Logarithm of the octanol/water distribution coefficient at pH 7.4log P Logarithm of the octanol/water partition coefficient for the neutral

specieslog Sw Logarithm of the aqueous solubilityMW Molecular weight

XIX