Metabolism of Drugs and Other Xenobiotics E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1392

Veröffentlichungsjahr: 2012

Beschreibung

A practice-oriented desktop reference for medical professionals, toxicologists and pharmaceutical researchers, this handbook provides
systematic coverage of the metabolic pathways of all major classes of xenobiotics in the human body. The first part comprehensively reviews
the main enzyme systems involved in biotransformation and how they are orchestrated in the body, while parts two to four cover the three
main classes of xenobiotics: drugs, natural products, environmental pollutants. The part on drugs includes more than 300 substances from
five major therapeutic groups (central nervous system, cardiovascular system, cancer, infection, and pain) as well as most drugs of abuse

including nicotine, alcohol and "designer" drugs. Selected, well-documented case studies from the most important xenobiotics classes illustrate general principles of metabolism, making this equally useful for teaching courses on pharmacology, drug metabolism or molecular
toxicology.
Of particular interest, and unique to this volume is the inclusion of a wide range of additional xenobiotic compounds, including food supplements, herbal preparations, and agrochemicals.

Leseprobe

Table of Contents

Cover

Related Titles

Title page

Copyright page

Preface

List of Contributors

Part One: Biochemistry and Molecular Genetics of Drug Metabolism

1 Drug-Metabolizing Enzymes – An Overview

1.1 Introduction: Fate of a Drug in the Human Body

1.2 Classification Systems of Drug-Metabolizing Enzymes According to Different Criteria

1.3 Overview of the Most Important Drug-Metabolizing Enzymes

Acknowledgments

2 Cytochromes P450

2.1 Introduction and Historical Perspective

2.2 Nomenclature and Gene Organization

2.3 Regulation

2.4 Polymorphisms

2.5 Protein Structure

2.6 Catalytic Mechanisms

2.7 What Determines P450 Catalytic Selectivity?

2.8 Oxidative Stress and P450s

2.9 Relevance in Drug Metabolism and Clinical Medicine

3 UDP-Glucuronosyltransferases

3.1 Introduction

3.2 A Simple Phenotype: Unconjugated Nonhemolytic Hyperbilirubinemia and Glucuronidation

3.3 Organization of UGTs and the UGT1A Gene Locus

3.4 UGT1A Gene Nomenclature

3.5 Human UGT1A Gene Locus and Sequence Variability

3.6 Glucuronidation of Bilirubin

3.7 UGT1A1 Gene

3.8 Is There an Advantage or Risk Associated with UGT1A1 Variability?

3.9 UGT1A1 Gene and Pharmacogenetic Protection

3.10 UGT1A1 Gene and Pharmacogenetic Risks

3.11 UGT1A1 Variability and Cancer Risk

3.12 UGT1A3 Gene

3.13 UGT1A7 Gene

3.14 Transcriptional Regulation of UGT1A Genes

3.15 Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A Genes

3.16 Regulation by Hepatic Nuclear Factors

3.17 Regulation by the Farnesoid X Receptor

3.18 Regulation by Nuclear Factor Erythroid 2-Related Factor 2

3.19 Regulation by Splice Variants

3.20 Animal Models to Study UGT1A Genes

3.21 Outlook

Acknowledgments

4 Sulfotransferases

4.1 Introduction

4.2 Background

4.3 PAPS Synthesis

4.4 SULT Enzyme Family

4.5 Assays for SULT Activity

4.6 Structure and Function of SULT

4.7 SULT Pharmacogenetics

4.8 Bioactivation and the Role of SULTs in Toxicology

4.9 Conclusions and Future Perspectives

5 Glutathione S-Transferases

5.1 Introduction and History

5.2 Nomenclature, Structure, and Function

5.3 Substrates

5.4 Regulation, Induction, and Inhibition

5.5 Gene Polymorphism of GSTs

6 Hydrolytic Enzymes

6.1 Carboxylesterases

6.2 Epoxide Hydrolases

6.3 Paraoxonases

6.4 Other Hydrolases

7 Transporting Systems

7.1 Introduction

7.2 Classification of Drug Transporters and Transport Mechanisms

7.3 Drug Transporters of the SLC Superfamily

7.4 ABC Drug Transporters

7.5 Drug Transporters and Disease

7.6 Drug Transporters and Pharmacokinetics

7.7 Role of Drug Transporters in Chemotherapy Resistance

7.8 Pharmacogenomics of Drug Transporters: Implications for Clinical Drug Response

Acknowledgments

8 Transcriptional Regulation of Human Drug-Metabolizing Cytochrome P450 Enzymes

8.1 Factors Affecting Drug-Metabolizing Cytochromes P450

8.2 Transcriptional Regulation of CYP

8.3 Regulation of Drug-Metabolizing CYPs

Acknowledgments

9 Importance of Pharmacogenomics

9.1 Introduction

9.2 Pharmacogenetic Polymorphisms

9.3 Polygenic and Multifactorial Aspects of Drug Metabolism Phenotype

9.4 Genomics Technologies and Approaches

9.5 Conclusions

Part Two: Metabolism of Drugs

10 Introduction to Drug Metabolism

10.1 Introduction

10.2 Historical Aspects

10.3 Diversity of Drug Metabolic Pathways

10.4 Influence of Drug Metabolism on Pharmacological Activity

10.5 Biotoxification

10.6 Extrahepatic Drug Metabolism

10.7 Factors Affecting Drug Metabolism Activity

10.8 Conclusions

11 Central Nervous System Drugs

11.1 Introduction

11.2 Antidepressants

11.3 Antipsychotics

11.4 Tranquillizers and Hypnotic Agents

11.5 Psychostimulants

11.6 Anticonvulsants and Mood Stabilizers

11.7 Agents for Dementia and Cognitive Enhancers

11.8 Antimigraine Drugs

11.9 Other Drugs

11.10 Conclusions

12 Cardiovascular Drugs

12.1 Introduction

12.2 RAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers

12.3 Adrenergic Receptor Agonists

12.4 Adrenergic Receptor Antagonists

12.5 Diuretics

12.6 Antiarrhythmics

12.7 Anticoagulants

12.8 Cholesterol-Lowering Drugs

13 Anticancer Drugs

13.1 Introduction

13.2 Alkylating Drugs

13.3 Platinum-Containing Agents

13.4 Antimetabolites

13.5 Natural Products

13.6 Endocrine Therapy

13.7 Histone Deacetylase Inhibitor (Vorinostat)

13.8 Tyrosine Kinase Inhibitors

13.9 Proteasome Inhibitor (Bortezomib)

14 Antimicrobial Agents

14.1 Introduction

14.2 Pharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial Agents

14.3 Pharmacogenetics

14.4 Conclusions

Acknowledgments

15 Drugs against Acute and Chronic Pain

15.1 Introduction

15.2 Acute Pain

15.3 Chronic Pain

16 Drugs of Abuse (Including Designer Drugs)

16.1 Introduction

16.2 Classic Drugs of Abuse

16.3 Designer Drugs of Abuse

17 Nicotine Metabolism and its Implications

17.1 Introduction

17.2 Absorption and Distribution of Nicotine

17.3 Excretion of Nicotine

17.4 Metabolism of Nicotine

17.5 Sources of Variation in Nicotine Metabolism

17.6 Implications of Variation in Nicotine Metabolism and CYP2A6 Activity

17.7 Conclusions

Acknowledgments

18 Metabolism of Alcohol and its Consequences

18.1 Introduction

18.2 Properties and Sources of Ethanol

18.3 Ethanol Absorption and Elimination

18.4 Ethanol Metabolism

Acknowledgments

Part Three: Metabolism of Natural Compounds

19 Introduction and Overview

19.1 Introduction

19.2 Terpenoids: A Structurally Complex Group of Natural Products

19.3 Other Classes of Natural Products

19.4 Summary and Conclusions

Acknowledgments

20 Flavonoids

20.1 Flavonoids – Plant Phytochemicals

20.2 Absorption and Metabolism of Flavonoids

20.3 Interactions of Flavonoids with Mammalian Proteins with Possible Implications for Drug Metabolism

20.4 Dietary Flavonoids – Health Issues

20.5 Flavonoid–Drug Interactions

20.6 Conclusion – Double-Edged Sword Properties of Flavonoids

21 St John’s Wort (Hypericum perforatum L.)

21.1 The Name Hypericum

21.2 Chemical Constituents of Hypericum perforatum

21.3 Clinical Pharmacology of H. perforatum

21.4 Pharmacokinetics and Pharmacokinetic Interactions of H. perforatum

21.5 In Vitro Studies

21.6 In Vivo Studies

Acknowledgments

22 Food Components and Supplements

22.1 Introduction

22.2 Food Contaminants

22.3 Vitamins

22.4 Macronutrients

22.5 Secondary Plant Metabolites

22.6 Probiotics and Prebiotics in the Modulation of Drug Metabolism

Part Four: Metabolism of Unnatural Xenobiotics

23 Environmental Pollutants

23.1 Introduction – An Overview

23.2 Overview of Environmental Pollutants

23.3 Toxic and Hazardous Environmental Pollutants Interacting with Drug Metabolism

23.4 Summary

24 Environmental Estrogens

24.1 Introduction

24.2 Estrogen Receptor Signaling Pathways

24.3 Agonistic/Antagonistic Effects of Xenobiotics on ERs

24.4 Effects of EDCs on Biosynthesis and Metabolism of Estrogens

24.5 Case of Polychlorinated Biphenyls

24.6 Conclusions

25 Biotransformation of Insecticides

25.1 Introduction to Insecticides

25.2 Metabolism of Insecticides

25.3 Extrahepatic Metabolism of Insecticides

25.4 Factors Affecting Metabolism

25.5 Conclusions

Note

Index

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The Editors

Prof. Pavel Anzenbacher

Palacky University at Olomouc

Dept. Pharmacology

Hnevotinska str. 3

779 00 Olomouc

Czech Republic

Prof. Dr. Ulrich M. Zanger

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstr. 112

70376 Stuttgart

Germany

Cover

Nabumetone bound in the active site of cytochrome P450 1A2 (Anzenbacherova, Berka et al., 17th Intl. Conference Cytochromes P450, Manchester 2011).

The structure has been supplied by Dr. Karel Berka.

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Preface

Lecturis salutem!

The editors of this new book, Metabolism of Drugs and Other Xenobiotics, are happy to greet all actual and prospective readers.

Why is drug metabolism of interest to so many researchers and medical professionals? Rudolf Buchheim, the founder of modern pharmacology, anticipated one of the major reasons as early as 1859:

In order to understand the actions of drugs it is an absolute necessity to have knowledge of the transformations they undergo in the body. It is obvious that we must not judge drugs according to the form and amount administered, but rather according to the form and amount which actually is eliciting the action.

(R. Buchheim, Lehrbuch der Arzneimittellehre, Voss, Leipzig, 1859, p. 19).

However, there are already quite a few books on drug metabolism – so why should there be another one?

One reason is, of course, that new drugs and other xenobiotic chemicals are constantly being produced by our industry; another is the pace of today’s science, which even in a more than a hundred-year-old discipline discovers new fascinating and important facts at exponential speed. However, the most compelling reason, at least to us, was the idea that came up during discussions with Frank Weinreich from Wiley VCH in 2009, to present this wildly complex topic of xenobiotic metabolism in a new and more practical way, that is, by drug class. The intention was to give readers the opportunity to get complete information on a given substance in one place (and not distributed among different chapters on enzymes and reactions), as well as to compare different substances in the same therapeutic group with respect to their metabolic pathways. Both can be of advantage, for example, to estimate pharmacokinetic variability based on the genetic and non-genetic factors that influence the involved enzyme(s), or to compare alternative drugs with respect to their biotransformation pathways. A further important aspect was not only to cover therapeutic drugs, but also to present a rather comprehensive overview of the xenobiotic chemical world, including recreational and abused drugs, natural plant and food constituents, as well as industrial chemicals and pollutants.

We divided the book’s 25 chapters into four parts: part I contains nine chapters that describe the major drug metabolizing enzyme and transporting protein systems, along with chapters that deal with general aspects of xenobiotic metabolism, regulation, and pharmacogenomics. Part II contains, after a general introduction, five chapters that describe the metabolism of over 300 clinically used drugs in five major therapeutic groups, as well as unique chapters on the two major socially accepted drugs, nicotine and alcohol, and an overview on illegal drugs of abuse. Part III presents the metabolism of natural compounds, such as plant terpenoids and flavonoids, in addition to food components and supplements, an often neglected area of growing importance. The final section then describes the metabolism of a wide variety of industrial products, environmental pollutants, and agrochemicals such as insecticides.

Nevertheless, the book is by no means exhaustive, and it does not cover the scope extensively, as this would not be possible in a single book. Thus, several important therapeutic areas are not included, and many other xenobiotics from different areas are unmentioned as well. Nevertheless, we hope that the selection we chose provides an interesting read and a useful desktop reference for a diverse spectrum of specialists and researchers, including clinical and experimental pharmacologists, pharmacists or toxicologists, as well as a helpful guide for those who try to find their way into this fascinating field. Although we did our best to avoid mistakes, omissions (particularly of important references), and inconsistencies, we apologize if you may find any.

We would like to express sincere thanks to our contributors. It was not an easy task to cover this broad field but we are confident that they are among the best experts in their fields, and we are very proud to have them as authors. We would also like to thank our co-workers and our families for their patience when we were deeply immersed in the preparation of our chapters and proofs, having even less time for them than usual. Last but not least, this book would not have been possible without the work of numerous people at Wiley VCH, and we would like to thank them all for their cooperation, patience, and tremendously good job.

Pavel Anzenbacher and Uli Zanger

Olomouc and Stuttgart, January 2012

List of Contributors

Pavel Anzenbacher

Palacky University at Olomouc

Faculty of Medicine and Dentistry

Department of Pharmacology and Inst. Mol. and Translational Medicine

Hnevotinska st. 3, Olomouc, 775 15

Czech Republic

Eva Anzenbacherová

Palacky University at Olomouc

Faculty of Medicine and Dentistry

Department of Medical Chemistry and Biochemistry

Hnevotinska st. 3, Olomouc, 775 15

Czech Republic

Pierre Baumann

Université de Lausanne

Centre Hospitalier Universitaire Vaudois

Department of Psychiatry

Site de Cery

1008 Prilly-Lausanne

Switzerland

Hiltrud Brauch

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Janet K. Coller

University of Adelaide

School of Medical Sciences

Discipline of Pharmacology

Adelaide, 5005

Australia

Michael W.H. Coughtrie

University of Dundee

Ninewells Hospital & Medical School

Medical Research Institute

Dundee, DD1 9SY, Scotland

UK

Alice L. Crane

State University of New York at Buffalo

Department of Pharmacology and Toxicology

Buffalo, NY 14214

USA

Chantal Csajka

University of Lausanne

University Hospital Center

Division of Clinical Pharmacology and Toxicology

1011 Lausanne

Switzerland

Laurent Decosterd

University of Lausanne

University Hospital Center

Division of Clinical Pharmacology and Toxicology

1011 Lausanne

Switzerland

Miroslav Dostalek

University of Rhode Island

College of Pharmacy

Department of Biomedical and Pharmaceutical Sciences

Clinical Pharmacokinetic Research Laboratory

41 Lower College Road

Kingston, RI 02881

USA

Simcyp Limited

Blades Enterprise Centre

John Street

S2 4SU Sheffield

UK

Zdenek Dvorak

Palacky University

Faculty of Science

Department of Cell Biology and Genetics

Slechtitelu 11

783 71 Olomouc

Czech Republic

Corie A. Ellison

State University of New York at Buffalo

Department of Pharmacology and Toxicology

Buffalo, NY 14214

USA

F. Peter Guengerich

Vanderbilt University School of Medicine

Department of Biochemistry and Center in Molecular Toxicology

638 Robinson Research Building

2200 Pierce Avenue

Nashville, TN 37232-0146

USA

Christoph Hiemke

Klinik für Psychiatrie und PsychotherapieUniversitätsmedizin Mainz

Untere Zahlbacher Str. 8

55131 Mainz

Germany

Petr Hodek

Charles University Prague

Department of Biochemistry

Albertov 2030

Prague, 128 40 Praha 2

Czech Republic

Sandra Kalthoff

Professor of Gastroenterology and Hepatology

Hannover Medical School

Department of Gastroenterology, Hepatology and Endocrinology

Carl-Neuberg-Str. 1

30625 Hannover

Germany

Kathrin Klein

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Miroslav Machala

Veterinary Research Institute

Department of Toxicology, Pharmacology and Immunotherapy

Hudcova 70

621 00 Brno

Czech Republic

Oriol Manuel

University Hospital Center

Service of Infectious Diseases and Transplantation Center

1011 Lausanne

Switzerland

Oscar Marchetti

University of Lausanne

University Hospital Center

Service of Infectious Diseases

1011 Lausanne

Switzerland

Hans H. Maurer

Saarland University

Institute of Experimental and Clinical Pharmacology and Toxicology

Department of Experimental and Clinical Toxicology

66421 Homburg (Saar)

Germany

Markus R. Meyer

Saarland University

Institute of Experimental and Clinical Pharmacology and Toxicology

Department of Experimental and Clinical Toxicology

66421 Homburg (Saar)

Germany

Sebastian Mueller

University of Heidelberg

Centre of Alcohol Research and Salem Medical Centre

Department of Medicine

Zeppelinstraße 11-33

69121 Heidelberg

Germany

Michael Murray

University of Sydney

Faculty of Pharmacy

Pharmacogenomics and Drug Development Group

Sydney, NSW 2006

Australia

Tadashi Namisaki

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Anne T. Nies

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

James R. Olson

State University of New York at Buffalo

Department of Pharmacology and Toxicology/Department of Social and Preventive Medicine

Buffalo, NY 14214

USA

Alexandr Parlesak

Technical University of Denmark

Department of Systems Biology

Søltofts Plads

Bldg. 224

2800 Lyngby

Denmark

Claudia Resch

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Stephan Riedmaier

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Jessica Rieger

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Elke Schaeffeler

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Matthias Schwab

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

and

Institute of Experimental and Clinical Pharmacology and Toxicology

Department of Clinical Pharmacology

University Hospital

Otfried-Müller-Str. 45

72076 Tübingen

Germany

Helmut K. Seitz

University of Heidelberg

Centre of Alcohol Research and Salem Medical Centre

Departement of Medicine

Zeppelinstraße 11-33

69121 Heidelberg

Germany

Andrew A. Somogyi

University of Adelaide

School of Medical Sciences

Discipline of Pharmacology

Adelaide, 5005

Australia

Anna-Katarina Stark

Karolinska Institutet

National Institute of Environmental Medicine

171 11 Stockholm

Sweden

Marie Stiborova

Charles University Prague

Department of Biochemistry

Albertov 2030

Prague, 128 40 Praha 2

Czech Republic

Christian P. Strassburg

Hannover Medical School

Department of Gastroenterology, Hepatology and Endocrinology

Carl-Neuberg-Str. 1

30625 Hannover

Germany

Amalio Telenti

University of Lausanne

University Hospital Center

Institute of Microbiology

1011 Lausanne

Switzerland

Rachel F. Tyndale

University of Toronto

Departments of Psychiatry, Pharmacology and Toxicology

Centre for Addiction and Mental Health

1 King’s College Circle

Toronto, Ontario M5S 1A8

Canada

Jan Vondráek

Veterinary Research Institute

Department of Toxicology

Hudcova 70

621 00 Brno

Czech Republic

Bingfang Yan

University of Rhode Island

Department of Biomedical and Pharmaceutical Sciences

Kingston, RI 02881

USA

Ulrich M. Zanger

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology

Auerbachstrasse 112

70376 Stuttgart

Germany

Andy Z.X. Zhu

University of Toronto

Departments of Psychiatry, Pharmacology and Toxicology

Centre for Addiction and Mental Health

1 King’s College Circle

Toronto, Ontario M5S 1A8

Canada

Part One: Biochemistry and Molecular Genetics of Drug Metabolism

1

Drug-Metabolizing Enzymes – An Overview

Pavel Anzenbacher and Eva Anzenbacherová

1.1 Introduction: Fate of a Drug in the Human Body

Drugs and, more generally, all substances foreign to the human body enter the organism in many ways. Intentional administration of a drug implies that the route of administration is selected depending on the clinical status of the patient, on the target tissue or organ, and on the chemical nature of the drug. For example, highly ionized compounds cannot easily penetrate barriers such as that of the gastrointestinal tract and therefore should be administered parenterally. Peptides or proteins are degraded to a great extent in the gastrointestinal tract by the action of hydrolytic enzymes and hence are often given to patients in ways other than the most common oral route (e.g., by intranasal application). Intravenous application implies an immediate interaction of a drug with plasma enzymes (e.g., carboxyesterases).

In many cases, the enzymes performing the biotransformation of a drug are needed to convert a parent drug (a prodrug) to the active molecule. Lovastatin – a hypolipidemic drug – is a good example of this process as it requires metabolic activation by carboxyesterases. Carboxyesterases in the plasma, liver microsomes, and liver cytosol convert 18, 15, and 67%, respectively, of the orally given drug to the active hydroxyacid molecule [1].

In general, after its administration a drug should be absorbed; subsequently, it is distributed in the body, often it is also metabolized, and finally excreted. These processes determine the pharmacokinetics of a drug; in other words, the time course of the drug level in the tissue or organ of interest.

The majority of drugs are administered orally and, hence, the uptake of a drug from the gastrointestinal tract is the most frequent way of drug absorption; consequently, the action of liver (and intestinal) drug-metabolizing enzymes starts already in the process of absorption, even before the drug reaches the systemic circulation. The enzymes of drug biotransformation often lower the amount of drug available in the systemic circulation by converting it into metabolites (active, inactive, or with an altered activity) – this process is known as the “first-pass effect.” The enzymes of drug biotransformation often decide the biological availability of a drug (i.e., the level of a drug available at the site of its action). This book focuses on drug metabolism and on the respective enzymes responsible for this process.

However, this is not the only role of drug-metabolizing enzymes. Changes in drug metabolism may be responsible for the incidence of adverse reactions to drugs, such as when a drug’s metabolism is blocked by another compound (e.g., due to competition with another drug – then the level of the “victim” drug may increase and even exceed the toxic levels) or, on the contrary, by induction of drug-metabolizing enzymes. Then, the metabolism of another drug (“victim”), metabolized by the same enzyme, is quicker and it may fail to reach its therapeutic range. This type of drug–drug interaction has been intensively studied as it is a potential reason for failure of pharmacotherapy [2]. The situation may be further heavily influenced by genetic predisposition of a patient to metabolize the respective drug, such as in many examples of drugs metabolized by cytochromes P450 (CYPs). This is, for example, the case for antidepressants metabolized by CYP form 2D6, where the genetically determined ability of a patient to metabolize the drug may lead to effective dose variations approaching an order of magnitude [3]. For example, when a slowly metabolizing patient on a somewhat lower dose of the “victim“ drug takes another drug metabolized by the same CYP2D6 enzyme, both the effects of drug interaction caused by the competition for the enzyme active site and the pharmacogenetic predisposition come into play, and the patient could easily be overdosed. This is why this book deals not only with the respective enzymes and drugs, but also with the pharmacogenetic implications of patients’ predispositions to variations in drug metabolism.