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    Genetic factors and co-prescribed drugs affecting pharmacotherapy

    Matthijs Lambertus Becker

  • Individualizing Pharmacotherapy

    Genetic factors and co-prescribed drugs affecting pharmacotherapy

    Matthijs Lambertus Becker

  • The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University

    Rotterdam, the Netherlands Organization for Scientific Research (NWO), the Netherlands

    Organization for Health Research and Development (ZonMW), the Research Institute for

    Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry

    of Health, Welfare and Sport, the European Commission (DG XII), and the Municipality of


    The contributions of the study participants, general practitioners and pharmacists of the

    Ommoord district to the Rotterdam Study are gratefully acknowledged.

    The work in this thesis was financially supported by the Inspectorate for Health Care.

    Cover: Linkage disequilibrium between single nucleotide polymorphisms in the SLC22A1

    gene, visually presented by the software package Graphical Overview of Linkage Disequilib-

    rium (GOLD), Center for Statistical Genetics, University of Michigan.

    Printed by Optima Grafische Communicatie, Rotterdam

    ISBN: 978-90-8559-574-8

    © Matthijs Lambertus Becker, 2009

    No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any

    form or by any means, without permission of the author, or, when appropriate, of the pub-

    lisher of the publications.



    Individualiseren van farmacotherapie

    De invloed van genetische factoren en co-medicatie op farmacotherapie


    ter verkrijging van de graad van doctor aan de

    Erasmus Universiteit Rotterdam

    op gezag van de

    rector magnificus

    Prof. dr. H.G. Schmidt

    en volgens besluit van het College voor Promoties.

    De openbare verdediging zal plaatsvinden op

    woensdag 4 november 2009 om 15.30 uur


    Matthijs Lambertus Becker

    geboren te Nijmegen

  • ProMotiecoMMissie

    Promotoren: Prof. dr. B.H.Ch. Stricker

    Prof. dr. A.G. Vulto

    Overige leden: Prof. dr. A.G. Uitterlinden

    Prof. dr. A. de Boer

    Prof. dr. P.A.B.M. Smits

    Copromotor: Dr. L.E. Visser

  • Contents chapter 1. General introduction 7

    chapter 2. co-prescribed drugs affecting pharmacotherapy 21

    Chapter 2.1. Increasing exposure to drug-drug interactions between 1992 and 2005 in people aged ≥55 years


    Chapter 2.2. Potential determinants of drug-drug interaction associated dispensing in community pharmacies: a literature review


    Chapter 2.3. Determinants of potential drug-drug interaction associated dispensing in community pharmacies in the Netherlands


    Chapter 2.4. Hospitalizations and emergency department visits due to drug-drug interactions: a literature review


    chapter 3. Genetic factors affecting pharmacotherapy for type 2 diabetes mellitus


    Chapter 3.1. Cytochrome P450 2C9 *2 and *3 polymorphisms and the dose and effect of sulfonylurea in type 2 diabetes mellitus


    Chapter 3.2. Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with type 2 diabetes mellitus


    Chapter 3.3. Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose lowering effect of metformin in patients with type 2 diabetes mellitus


    Chapter 3.4. Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response


    Chapter 3.5. Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea


    chapter 4. Genetic factors affecting cardiovascular pharmacotherapy 141

    Chapter 4.1. Common genetic variation in the ABCB1 gene is associated with the cholesterol lowering effect of simvastatin in males


    Chapter 4.2. Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy


    Chapter 4.3. Genetic variation in the NOS1AP gene is associated with the incidence of diabetes mellitus in users of calcium channel blockers


    Chapter 4.4. A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers


  • chapter 5. Genetic factors affecting pharmacotherapy for Parkinson’s disease 189

    Chapter 5.1. The OCT1 polymorphism rs622342 A>C is associated with decreased drug response and shorter survival time in Parkinson’s disease


    chapter 6. General discussion 203

    chapter 7. summary 225

    Chapter 7.1. Summary 227

    Chapter 7.2. Samenvatting voor niet ingewijden 233

    Abbreviations 241

    Dankwoord 243

    Bibliography 247

    PhD portfolio 251

    About the author 253

  • Chapter 1. General introduction

  • 11

    General introduction


    The goal of pharmacotherapy is, in general, to cure a disease or to eliminate or reduce

    symptoms. In daily practice, predefined goals of pharmacotherapy are often not met for

    various reasons, such as ineffectiveness of the drug or adverse drug reactions. Estimations

    of the proportion of patients without clinically significant efficacy to important classes of

    therapeutic drugs range from 30 to 60 percent.[1] Conversely, around two to four percent

    of all hospital admissions result from adverse drug reactions with a quarter to half of these

    admissions being preventable.[2-4] In the United States, adverse drug reactions are the fourth

    leading cause of hospitalization and result in roughly 100.000 deaths annually.[5,6]

    Many factors are involved in the variation in drug response and a better understanding of

    these factors can improve the effectiveness of pharmacotherapy and reduce the incidence

    of adverse drug reactions. Healthcare relies, more often than is desirable, on the ‘one-dose-

    fits-all’ approach. The initial starting dose is the same for all patients, irrespective of the

    patient’s individual characteristics. Personalized medicine, or tailoring drug therapy to the

    characteristics of the individual patient, is a useful tool in reducing the number of ineffective

    therapies and adverse drug reactions.[5]

    PharMacokinetics and PharMacodynaMics

    The process from drug intake to drug response is complicated, and many factors are in-

    volved. A distinction can be made between pharmacokinetic and pharmacodynamic factors.

    Pharmacokinetics concerns the fate of a drug when it is administered to the body. The first

    part of the pharmacokinetic process consists of the absorption of the drug into the body,

    distribution throughout the body tissues and fluids and then subsequent elimination. Dur-

    ing these stages, some drugs can diffuse through membranes passively, without the help

    of energy consuming enzymes. These drugs are in most cases uncharged, lipophilic and

    unbound. Other drugs cannot cross membranes passively and rely on active carriage by

    transporter proteins. A large number of different transporter proteins are present throughout

    the body and regulate the plasma levels of substances in tissues and fluids.[7-9] Two important

    transporter families are the ATP Binding Cassette (ABC) family and the solute carrier (SLC)

    family. These two families have important roles in the pharmacokinetics of both drugs and

    endogenous compounds.[10-12]

    The second part of the pharmacokinetic process is the irreversible transformation of drugs

    into metabolites. Metabolism is divided into two phases. In phase I, drugs are metabolized

    into more water-soluble substances through oxidation and reduction. The main phase I

    metabolizing enzymes are the cytochrome P450 (CYP) enzymes, although other enzymes

    such as xanthine oxidase (metabolizing 6-mercaptopurine) and alcohol dehydrogenase

  • Chapter 1.


    (metabolizing ethanol) are also involved.[13-15] The CYP enzymes are responsible for around 75

    percent of total drug metabolism.[13]

    The phase II metabolizing enzymes conjugate polar groups, such as glucuronyl (UDP

    glucoronosyltransferases, UGT) and acetyl (acetyl-CoA) to apolar substances.[15,16] These reac-

    tions result in a further increase in hydrophilicity and a more efficient excretion by the kidney

    or on some occasions via bile secretion. Most drugs are inactivated by phase I and phase

    II reactions, although some drugs, such as codeine and tamoxifen, are administered as the

    inactive pro-drug and metabolized to the active compound.[17,18]

    Besides pharmacokinetics, pharmacodynamics plays a major role in drug response. Phar-

    macodynamics relates to the biochemical or physiological effects of a drug on the body.

    One of the mechanisms of pharmacodynamics is the