Pharmacokinetics and Metabolism in Drug Design E-Book

Dennis A. Smith

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 424

Veröffentlichungsjahr: 2012

Beschreibung

In this new edition of a bestseller, all the contents have been brought upto-date by addressing current standards and best practices in the assessment and prediction of ADMET properties. Although the previous chapter layout has been retained, substantial revisions have been made, with new topics such as pro-drugs, active metabolites and transporters covered in detail in a manner useful to the Drug Discovery scientist. The authors discuss the 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.

While aimed at all those dealing professionally with the development and application of pharmaceutical substances, the readily comprehensible style makes this book equally suitable for students of pharmacy and related subjects. Uniquely comprehensive, the book relates physicochemistry and chemical structure to pharmacokinetic properties and ultimately drug efficacy and safety.

Leseprobe

Contents

Cover

Methods and Principles in Medicinal Chemistry

Title Page

Copyright

A Personal Foreword

Chapter 1: Physicochemistry

Abbreviations

Symbols

1.1 Physicochemistry and Pharmacokinetics

1.2 Partition and Distribution Coefficients as Measures of Lipophilicity

1.3 Limitations on the Use of 1-Octanol

1.4 Further Understanding of log P

1.5 Alternative Lipophilicity Scales

1.6 Computational Systems to Determine Lipophilicity

1.7 Membrane Systems to Study Drug Behavior

1.8 Dissolution and Solubility

1.9 The BCS Classification and Central Role of Permeability

Chapter 2: Pharmacokinetics

Abbreviations

Symbols

2.1 Setting the Scene

2.2 Intravenous Administration: Volume of Distribution

2.3 Intravenous Administration: Clearance

2.4 Intravenous Administration: Clearance and Half-life

2.5 Intravenous Administration: Infusion

2.6 Oral Administration

2.7 Repeated Doses

2.8 Development of the Unbound (Free) Drug Model

2.9 Unbound Drug and Drug Action

2.10 Unbound Drug Model and Barriers to Equilibrium

2.11 Pharmacodynamic Models

2.12 Slow Offset Compounds

2.13 Factors Governing Unbound Drug Concentration

Chapter 3: Absorption

Abbreviations

Symbols

3.1 The Absorption Process

3.2 Dissolution

3.3 Membrane Transfer

3.4 Barriers to Membrane Transfer

3.5 Prodrugs to Increase Oral Absorption

3.6 Active Transport

3.7 Models for Absorption Estimation

3.8 Estimation of Absorption Potential and other Computational Approaches

Chapter 4: Distribution

Abbreviations

Symbols

4.1 Membrane Transfer Access to the Target

4.2 Brain Penetration

Chapter 5: Clearance

Abbreviations

Symbols

5.1 The Clearance Processes

5.2 Role of Transport Proteins in Drug Clearance

5.3 Interplay Between Metabolic and Renal Clearance

5.4 Role of Lipophilicity in Drug Clearance

5.5 Active Metabolites

5.6 Balancing the Rate of Renal and Metabolic clearance and Potency

Chapter 6: Renal Clearance

Abbreviations

Symbols

6.1 Kidney Anatomy and Function

6.2 Lipophilicity and Reabsorption by the Kidney

6.3 Effect of Charge on Renal Clearance

6.4 Plasma Protein Binding and Renal Clearance

6.5 Balancing Renal Clearance and Absorption

6.6 Renal Clearance and Drug Design

Chapter 7: Metabolic (Hepatic) Clearance

Abbreviations

7.1 Symbols

7.2 Function of Metabolism (Biotransformation)

7.3 Cytochrome P450

7.4 Other Oxidative Metabolism Processes

7.5 Oxidative Metabolism and Drug Design

7.6 Nonspecific Esterases

7.7 Prodrugs to Aid Membrane Transfer

7.8 Enzymes Catalyzing Drug Conjugation

7.9 Stability to Conjugation Processes

7.10 Pharmacodynamics and Conjugation

Chapter 8: Toxicity

Abbreviations

8.1 Toxicity Findings

8.2 Structure–Toxicity Analyses

8.3 Reactive Metabolite Screening in Drug Discovery

8.4 Structural Alerts/Toxicophores in Drug Design

8.5 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Effect of Daily Dose

8.6 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Competing Detoxication Pathways

8.7 Stratification of Toxicity

8.8 Toxicity Prediction: Computational Toxicology

8.9 Toxicogenomics

8.10 Pharmacogenomics

8.11 Enzyme Induction and Drug Design

8.12 Enzyme Inhibition and Drug Design

Chapter 9: Predicting Human Pharmacokinetics

Abbreviations

Symbols

9.1 Objectives of Predicting Human Pharmacokinetics

9.2 Allometric Scaling of Preclinical In Vivo PK Parameters

9.3 Prediction of Human PK Parameters Using In Vitro Data

9.4 Elimination Half-Life

9.5 Moving Forward

Chapter 10: ADME Screening

Abbreviations

Symbols

10.1 The High-Throughput Synthesis and Screening Trend

10.2 The Concept of ADME Space

10.3 Drug Metabolism and Discovery Screening Sequences

10.4 Physicochemistry

10.5 Absorption/Permeability

10.6 Metabolism, Induction, and Inhibition

10.7 Transporters

10.8 Protein Binding

10.9 Pharmacokinetics

10.10 In silico Approaches to ADME

Index

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. FolkersEditorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

De Clercq, Erik (Ed.)Antiviral Drug Strategies2011ISBN: 978-3-527-32696-9Vol. 50

Klebl, Bert / Müller, Gerhard / Hamacher, Michael (Eds.)Protein Kinases as Drug Targets2011ISBN: 978-3-527-31790-5 Vol. 49

Sotriffer, Christoph (Ed.)Virtual ScreeningPrinciples, Challenges, and Practical Guidelines2011ISBN: 978-3-527-32636-5Vol. 48

Rautio, Jarkko (Ed.)Prodrugs and Targeted DeliveryTowards Better ADME Properties2011ISBN: 978-3-527-32603-7Vol. 47

Smit, Martine J. / Lira, Sergio A. / Leurs, Rob (Eds.)Chemokine Receptors as DrugTargets2011ISBN: 978-3-527-32118-6Vol. 46

Ghosh, Arun K. (Ed.)Aspartic Acid Proteases asTherapeutic Targets2010ISBN: 978-3-527-31811-7Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)Transporters as Drug CarriersStructure, Function, Substrates2009ISBN: 978-3-527-31661-8Vol. 44

Faller, Bernhard / Urban, Laszlo (Eds.)Hit and Lead ProfilingIdentification and Optimization of Drug-like Molecules2009ISBN: 978-3-527-32331-9Vol. 43

Sippl, Wolfgang / Jung, Manfred (Eds.)Epigenetic Targets in Drug Discovery2009ISBN: 978-3-527-32355-5Vol. 42

Todeschini, Roberto / Consonni, VivianaMolecular Descriptors for ChemoinformaticsVolume I: Alphabetical Listing / Volume II: Appendices, References2009ISBN: 978-3-527-31852-0Vol. 41

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A Personal Foreword

Time seems to have passed so quickly since we updated the second edition, but as we began to assemble the list of changes and incorporations we needed to make for the third edition, we realized just how much the science has moved on. It really was time to renew the book and keep it at the forefront of the application of pharmacokinetics and metabolism in drug design. Not only the science had moved on, though, but also the people and finally the actual workplace.

In this edition, more attention is paid to the role of drug permeability in determining ADME fate. Much more emphasis is also placed on drug transport (in parallel to permeability). In addition, the role of free drug is described more fully. The latest concepts and knowledge in drug distribution, drug clearance, and drug toxicity are incorporated along with more descriptive sections on human prediction and screening methods. What has not changed is the layout of chapters, trying to condense the huge breadth of topics covered under a readable size. Each chapter can be read alone or in sequence. We hope readers who attempt the sequence find it not a sprint, not a marathon, but a satisfying middle distance: more magic mile than magic methyl.

Han and Don took retirement shortly before the third edition project began and Amit and Charlotte have stepped into their place as authors. Both have very strong chemistry backgrounds, with Charlotte a practicing and distinguished medicinal chemist before stepping across into the land of uncertainty and promise (ADME), and Amit is recognized worldwide for his experience in enzymology and metabolism chemistry. Don and Han have not disappeared, they have worked meticulously on the various chapter proofs, ensuring what we thought we had clearly written could actually be comprehended by the reader.

Finally the workplace. What brought us together was Pfizer Drug Metabolism (or Pharmacokinetics, Dynamics and Metabolism as it became known later). The original trio of authors of the first and second editions worked together at Sandwich Laboratories. The year 2011 marked the closure of Drug Discovery at Sandwich. The laboratories that buzzed with the electrical energy of drug discovery creating doxazosin, fluconazole, amlodipine, voriconazole, eletriptan, sildenafil, maraviroc, and more now are almost deserted. I feel, as they do, that working at Sandwich during its almost magical productive period was a privilege that left us with a profound sense of achievement. Charlotte too was Sandwich based, and I would like to dedicate the third edition to the people who made the Sandwich site so special in terms of drug discovery and drug metabolism. It will remain in the memory as a crucible of many of the thoughts and ideas in this book.

Dennis A. Smith

Chapter 1

Physicochemistry

Abbreviations

CPCCentrifugal partition chromatographyCoMFAComparative field analysisCsACyclosporine A3D-QSARThree-dimensional quantitative structure–activity relationshipsHDMHexadecane membraneIUPACInternational Union of Pure and Applied ChemistryMLPMolecular lipophilicity potentialPAMPAParallel artificial membrane permeability assayPGDPPropylene glycol dipelargonatePSAPolar surface areaRP-HPLCReversed-phase high-performance liquid chromatographySFShake flask, referring to traditional method of measuring log P or log DTPSATopological polar surface are

Symbols

APSUVAbsorption potential measured in small unilamellar vesicles (SUV)Δlog DDifference between log D in octanol/water and log D in alkane/waterΔlog PDifference between log P in octanol/water and log P in alkane/waterfRekker or Leo/Hansch fragmental constant for log P contributionKaIonization constantΛPolarity term, mainly related to hydrogen bonding capability of a solutelog PLogarithm of the partition coefficient (P) of neutral specieslog DLogarithm of the distribution coefficient (D) at a selected pH, usually assumed to be measured in octanol/waterlog DoctLogarithm of the distribution coefficient (D) at a selected pH, measured in octanol/waterlog DchexLogarithm of the distribution coefficient (D) at a selected pH, measured in cyclohexane/waterlog D7.4Logarithm of the distribution coefficient (D) at pH 7.4MWMolecular weightπHansch constant; contribution of a substituent to log PpKaNegative logarithm of the ionization constant Ka

1.1 Physicochemistry and Pharmacokinetics

The body can be viewed as primarily composed of a series of membrane barriers dividing aqueous filled compartments. These membrane barriers are principally comprised of the phospholipid bilayers that surround cells and form intracellular barriers around the organelles present in cells (mitochondria, nucleus, etc.). These are formed with the polar ionized head groups of the phospholipid facing toward the aqueous phases and the lipid chains providing a highly hydrophobic inner core. To cross the hydrophobic inner core, a molecule must also be hydrophobic and able to shed its hydration sphere. Many of the processes of drug disposition depend on the ability or inability to cross membranes and hence there is a high correlation with measures of lipophilicity. Moreover, many of the proteins involved in drug disposition have hydrophobic binding sites further adding to the importance of the measures of lipophilicity [1].

At this point, it is appropriate to define the terms hydrophobicity and lipophilicity. According to published IUPAC recommendations, both terms are best described as follows [2]:

Hydrophobicity is the association of nonpolar groups or molecules in an aqueous environment that arises from the tendency of water to exclude nonpolar molecules.

Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behavior in a biphasic system, either liquid–liquid (e.g., partition coefficient in 1-octanol/water) or solid–liquid (retention on reversed-phase high-performance liquid chromatography or thin-layer chromatography (TLC) system).

Key physicochemical properties that are associated with hydrophobicity and lipophilicity include solubility, hydrogen bonding capacity, and the ionization state [3]. All these properties have a strong influence on membrane permeability that affects absorption [4], distribution, and balance of elimination by transporter-mediated processes and metabolism [5].