DRUG EPIDEMIOLOGY, INTERACTIONS AND PHARMACOGENETICS A post-mortem database study

.........................................................................................................................................................8 INTRODUCTION............................................................................................................................................10 REVIEW OF THE LITERATURE ..............................................................................................................11 1 Pharmacotherapy ...............................................................................................................................11 1.1 Adverse drug reactions and events ....................................................................................11 1.2 Drug-drug interactions ............................................................................................................12 1.2.1 Interactions of warfarin ..................................................................................................14 2 Pharmacogenetics ..............................................................................................................................16 2.1 CYP enzymes ................................................................................................................................16 2.1.1 CYP2D6 ..................................................................................................................................18 2.1.2 CYP3A4 ..................................................................................................................................18 2.2 Clinical pharmacogenetics .....................................................................................................18 2.3 Venlafaxine metabolism and pharmacogenetics ..........................................................19 2.4 Post-mortem pharmacogenetics .........................................................................................21 3 Epidemiology and public health ...................................................................................................22 3.1 Pharmacovigilance and -epidemiology ............................................................................22 3.2 Substance abuse .........................................................................................................................23 3.3 Post-mortem pharmacoepidemiology ..............................................................................23 3.3.1 Drug toxicity ........................................................................................................................24 3.3.2 Fatal toxicity index ............................................................................................................24 AIMS OF THE STUDY ..................................................................................................................................26 MATERIALS AND METHODS ...................................................................................................................27 1 Autopsy cases .......................................................................................................................................27 1.1 Samples ..........................................................................................................................................27 1.2 Post-mortem database .............................................................................................................27 2 Data refining ..........................................................................................................................................27 2.1 SFINX ...............................................................................................................................................27 2.2 Case selection criteria ..............................................................................................................28 3 Analysis methods ................................................................................................................................29 3.1 Analysis of acidic and neutral drugs ..................................................................................29 3.2 Metabolite analysis ....................................................................................................................30 4 Genotyping .............................................................................................................................................30 4.1 CYP2D6 allele activity scores, genotype classes and phenotypes .........................30 5 Statistical methods .............................................................................................................................31 RESULTS ...........................................................................................................................................................32 1 Prevalence of adverse drug combinations ...............................................................................32 1.1 Drug combinations with a pharmacodynamic interaction mechanism .............32 1.2 Drug combinations with a pharmacokinetic interaction mechanism .................32 1.3 Death certificates .......................................................................................................................32 2 Concomitant use of warfarin and paracetamol ......................................................................33 2.1 Post-mortem warfarin concentrations .............................................................................33 3 Venlafaxine findings and fatalities ...............................................................................................33 3.1 Pharmacogenetics ......................................................................................................................33 3.1.1 Allele and phenotype frequencies ..............................................................................33 3.1.2 CYP2D6 and venlafaxine metabolite ratios ............................................................33 3.2 Concentrations ............................................................................................................................34 3.3 Drug interactions........................................................................................................................34 3.4 Venlafaxine in comparison with other antidepressants ............................................35 4 Nicotine in deceased young adults ..............................................................................................35 4.1 Prevalence of nicotine findings ............................................................................................35 4.2 Nicotine and substance abuse ..............................................................................................35 4.3 Nicotine and psychopharmaceuticals ...............................................................................36 4.4 Nicotine and manner of death ..............................................................................................36 DISCUSSION ...................................................................................................................................................37 1 Methodological considerations .....................................................................................................37 1.1 The Finnish post-mortem toxicology database .............................................................37 1.2 Post-mortem pharmacology ..................................................................................................37 1.3 Drug selection ..............................................................................................................................40 1.4 Genotyping ....................................................................................................................................41 2 Prevalence of adverse drug combinations ...............................................................................41 3 Safety of warfarin and paracetamol combination .................................................................44 4 Venlafaxine toxicity ............................................................................................................................45 5 Nicotine and substance abuse .......................................................................................................47 CONCLUSIONS ...............................................................................................................................................49 ACKNOWLEDGEMENTS ............................................................................................................................50 REFERENCES .................................................................................................................................................52