Pharmacokinetic Interactions of Pioglitazone

........................................................................................................................................................ INTRODUCTION........................................................................................................................................... REVIEW OF THE LITERATURE............................................................................................................... 1. Pharmacokinetics and drug interactions........................................................................................... 1.1. Drug metabolism...................................................................................................................... 1.2. CYP enzymes.............................................................................................................................. 1.2.1. CYP1A subfamily ..................................................................................................... 1.2.2. CYP2A6........................................................................................................................ 1.2.3. CYP2B6........................................................................................................................ 1.2.4. CYP2C subfamily...................................................................................................... 1.2.5. CYP2D6........................................................................................................................ 1.2.6. CYP2E1......................................................................................................................... 1.2.7. CYP3A subfamily...................................................................................................... 1.3. Induction and inhibition of CYP enzymes....................................................................... 1.3.1. Mechanisms of induction..................................................................................... 1.3.2. Mechanisms of inhibition..................................................................................... 1.4. Drug transporters..................................................................................................................... 2. Pioglitazone................................................................................................................................................. 2.1. Pharmacodynamics and clinical use.................................................................................. 2.2. Pharmacokinetics and drug interactions......................................................................... 2.3. Adverse eff ects........................................................................................................................... 3. Drugs studied with pioglitazone in vivo........................................................................................... 3.1. Rifampicin.................................................................................................................................... 3.2. Itraconazole................................................................................................................................. 3.3. Gemfi brozil.................................................................................................................................. 3.4. Montelukast and zafi rlukast.................................................................................................. 3.5. Repaglinide................................................................................................................................. AIMS OF THE STUDY....................................................................................................................................... MATERIALS AND METHODS........................................................................................................................ 1. In vitro study (Study I)............................................................................................................................... 1.1. Microsomes and recombinant CYP enzymes................................................................. 1.2. Incubation conditions............................................................................................................. 1.3. Pioglitazone metabolism and inhibition experiments................................................ 1.4. Determination of IC50 values of CYP2C8 inhibitors....................................................... 1.5. Determination of pioglitazone and metabolite concentrations.............................. 2. In vivo studies (Studies II-V).................................................................................................................... 2.1. Subjects........................................................................................................................................ 6