Studies on Drug Interactions between CYP 3 A 4 Inhibitors and Glucocorticoids by Tiina Varis

............................................................................................................................8 INTRODUCTION ...................................................................................................................9 REVIEW OF THE LITERATURE......................................................................................10 1. Drug metabolism.............................................................................................................10 1.1. Principles of drug metabolism.................................................................................10 1.2. The CYP enzymes...................................................................................................10 1.3. CYP3A subfamily ...................................................................................................11 1.4. Drug interactions .....................................................................................................14 1.5. Drug interactions mediated by inhibition of CYP3A4 ............................................16 1.6. CYP3A4 inhibitors studied .....................................................................................17 1.6.1. Itraconazole..........................................................................................................17 1.6.2. Diltiazem..............................................................................................................18 1.6.3. Mibefradil.............................................................................................................20 1.6.4. Grapefruit juice ....................................................................................................21 1.7. CYP3A4 and P-glycoprotein...................................................................................24 2. Glucocorticoids...............................................................................................................24 2.1. General ....................................................................................................................24 2.2. Regulation of cortisol secretion...............................................................................27 2.3. Pharmacodynamics..................................................................................................27 2.4. Therapeutic use .......................................................................................................28 2.5. Adverse effects of glucocorticoid treatment............................................................30 2.6. Methylprednisolone.................................................................................................30 2.7. Prednisolone............................................................................................................33 2.8. Dexamethasone .......................................................................................................35 AIMS OF THE STUDY ........................................................................................................38 MATERIALS AND METHODS ..........................................................................................39 1. Ethical considerations .....................................................................................................39 2. Study subjects .................................................................................................................39 3. Study protocol.................................................................................................................39 3.1. Study design ............................................................................................................39 3.2. Determination of plasma drug and cortisol concentrations .....................................42 3.3. Pharmacokinetic calculations ..................................................................................43 3.4. Pharmacodynamic measurements............................................................................44 3.5. Statistical methods...................................................................................................45 3.6. Archiving.................................................................................................................45