P-glycoprotein and chiral antidepressant drugs: Pharmacokinetic, pharmacogenetic and toxicological aspects

.................................................................................................... 9 POPULÄRVETENSKAPLIG SAMMANFATTNING ............................. 11 ABBREVIATIONS ....................................................................................... 13 INTRODUCTION ......................................................................................... 15 PSYCHOPHARMACOLOGY....................................................................................... 15 TOXICOLOGY ........................................................................................................... 19 CHIRALITY ............................................................................................................... 20 CHIRAL ANTIDEPRESSANT DRUGS ........................................................................ 22 Venlafaxine ................................................................................................................................ 22 Citalopram and Escitalopram ................................................................................................. 25 BLOOD-BRAIN BARRIER ......................................................................................... 27 ABC transport proteins ............................................................................................................ 29 P-GLYCOPROTEIN .................................................................................................... 31 In vitro and in vivo P-gp studies ............................................................................................ 33 AIMS OF THE THESIS ............................................................................... 35 MATERIALS AND METHODS ................................................................. 37 ANIMAL STUDIES (PAPERS I-III) .......................................................................... 37 Animals ....................................................................................................................................... 37 Drug administration and sample collection ......................................................................... 37 Acute administration ........................................................................................................... 37 Chronic administration ....................................................................................................... 38 Chiral determination of drugs ................................................................................................. 38 Venlafaxine and metabolites .............................................................................................. 38 Citalopram and metabolites .............................................................................................. 39 Open-field behavior (Paper II) ............................................................................................... 40 Statistics ...................................................................................................................................... 41 Ethics committee permission .................................................................................................. 41 FORENSIC STUDY (PAPER IV)................................................................................ 42 Case selection............................................................................................................................. 42 Genotyping ................................................................................................................................. 42 Statistics ...................................................................................................................................... 43 Ethics committee permission .................................................................................................. 43 RESULTS AND DISCUSSION ................................................................... 45 ANIMAL STUDIES (PAPERS I-III) ........................................................................... 45 Pharmacokinetics ...................................................................................................................... 45 Pharmacodynamics ................................................................................................................... 51 FORENSIC STUDY (PAPER IV)................................................................................ 53 CONCLUSIONS ............................................................................................ 59 ANIMAL STUDIES (PAPERS I-III) ........................................................................... 59 FORENSIC STUDY (PAPER IV)................................................................................ 60 FUTURE ASPECTS ..................................................................................... 61 ACKNOWLEDGEMENTS .......................................................................... 63 REFERENCES .............................................................................................. 67 APPENDIX (PAPERS I-IV) ......................................................................... 89