Department of Clinical Pharmacology University of Helsinki Finland PHARMACOKINETIC INTERACTIONS OF PIOGLITAZONE Tiina Jaakkola ACADEMIC DISSERTATION To be presented, with the permission of the Medical Faculty of the University of Helsinki, for public examination in Auditorium 2 of Biomedicum, on August 24th, 2007, at 12 noon. Helsinki 2007 JJaakkola_Tiina_vaitos.inddaakkola_Tiina_vaitos.indd 1 117.7.20077.7.2007 221:11:231:11:23 Supervisors: Professor Pertti Neuvonen, MD Department of Clinical Pharmacology University of Helsinki Helsinki, Finland Docent Janne Backman, MD Department of Clinical Pharmacology University of Helsinki Helsinki, Finland Reviewers: Docent Kimmo Malminiemi, MD, MSc Department of Pharmacology, Clinical Pharmacology and Toxicology University of Tampere Tampere, Finland Professor emeritus Pertti Pentikäinen, MD Department of Medicine University of Helsinki Helsinki, Finland Opponent: Professor Kari Kivistö, MD Department of Pharmacology, Clinical Pharmacology and Toxicology University of Tampere Tampere, Finland ISBN 978-952-92-2224-7 (paperback) ISBN 978-952-10-4020-7 (PDF, http://ethesis.helsinki.fi ) Helsinki 2007 Yliopistopaino JJaakkola_Tiina_vaitos.inddaakkola_Tiina_vaitos.indd 2 117.7.20077.7.2007 221:11:551:11:55 JJaakkola_Tiina_vaitos.inddaakkola_Tiina_vaitos.indd 3 117.7.20077.7.2007 221:11:551:11:55 CONTENTS CONTENTS ABBREVIATIONS.......................................................................................................................................... 6 LIST OF ORIGINAL PUBLICATIONS........................................................................................................ 7 ABSTRACT......................................................................................................................................................... 8 INTRODUCTION........................................................................................................................................... 10 REVIEW OF THE LITERATURE............................................................................................................... 12 1. Pharmacokinetics and drug interactions........................................................................................... 12 1.1. Drug metabolism...................................................................................................................... 12 1.2. CYP enzymes.............................................................................................................................. 13 1.2.1. CYP1A subfamily ..................................................................................................... 14 1.2.2. CYP2A6........................................................................................................................ 14 1.2.3. CYP2B6........................................................................................................................ 14 1.2.4. CYP2C subfamily...................................................................................................... 16 1.2.5. CYP2D6........................................................................................................................ 17 1.2.6. CYP2E1......................................................................................................................... 17 1.2.7. CYP3A subfamily...................................................................................................... 18 1.3. Induction and inhibition of CYP enzymes....................................................................... 18 1.3.1. Mechanisms of induction..................................................................................... 19 1.3.2. Mechanisms of inhibition..................................................................................... 20 1.4. Drug transporters..................................................................................................................... 20 2. Pioglitazone................................................................................................................................................. 21 2.1. Pharmacodynamics and clinical use.................................................................................. 21 2.2. Pharmacokinetics and drug interactions......................................................................... 22 2.3. Adverse eff ects........................................................................................................................... 24 3. Drugs studied with pioglitazone in vivo........................................................................................... 25 3.1. Rifampicin.................................................................................................................................... 25 3.2. Itraconazole................................................................................................................................. 26 3.3. Gemfi brozil.................................................................................................................................. 27 3.4. Montelukast and zafi rlukast.................................................................................................. 28 3.5. Repaglinide................................................................................................................................. 29 AIMS OF THE STUDY....................................................................................................................................... 30 MATERIALS AND METHODS........................................................................................................................ 31 1. In vitro study (Study I)............................................................................................................................... 31 1.1. Microsomes and recombinant CYP enzymes................................................................. 31 1.2. Incubation conditions............................................................................................................. 31 1.3. Pioglitazone metabolism and inhibition experiments................................................ 31 1.4. Determination of IC50 values of CYP2C8 inhibitors....................................................... 32 1.5. Determination of pioglitazone and metabolite concentrations.............................. 32 2. In vivo studies (Studies II-V).................................................................................................................... 33 2.1. Subjects........................................................................................................................................ 33 JJaakkola_Tiina_vaitos.inddaakkola_Tiina_vaitos.indd 4 117.7.20077.7.2007 221:11:551:11:55 CONTENTS 2.2. Study design............................................................................................................................... 34 2.3. Blood and urine sampling...................................................................................................... 35 2.4. Determination of plasma and urine drug concentrations......................................... 35 2.4.1. Pioglitazone and pioglitazone metabolites................................................... 35 2.4.2. Gemfi brozil, itraconazole and hydroxyitraconazole (Study II)................. 36 2.4.3. Montelukast and zafi rlukast (Study III)............................................................. 36 2.4.4. Repaglinide (Study V)............................................................................................. 36 2.5. Pharmacokinetic calculations............................................................................................... 36 2.6. Pharmacodynamic measurements .................................................................................... 37 2.7. In vitro-in vivo interaction predictions.............................................................................. 38 2.8. Statistical analysis..................................................................................................................... 38 RESULTS................................................................................................................................................................... 39 1. Metabolism of pioglitazone in vitro (Study I)................................................................................... 39 2. Eff ects of gemfi brozil and itraconazole on pioglitazone (Study II).......................................... 40 2.1. Pioglitazone pharmacokinetics in plasma....................................................................... 40 2.2. Pioglitazone metabolites in plasma................................................................................... 42 2.3. Excretion of pioglitazone and its metabolites in urine................................................ 42 2.4. Gemfi brozil, itraconazole and hydroxyitraconazole concentrations..................... 42 3. Eff ects of montelukast and zafi rlukast on pioglitazone (Study III)........................................... 42 3.1. Pioglitazone pharmacokinetics in plasma....................................................................... 42 3.2. Pioglitazone metabolites in plasma................................................................................... 43 3.3. Montelukast and zafi rlukast concentrations................................................................... 43 4. Eff ect of rifampicin on pioglitazone (Study IV)..............................................................................