Cel To continue molecular genetic studies on genes encoding the most important enzymes involved in the disposition of psychotropic drugs; to study these enzymes from in vitro to in vivo in different genotype groups of different nationalities. To study relationship between genotype, drug plasma concentration and therapeutic as wells as side-effects during treatment of mental disorders. To investigate the molecular background to adverse drug reactions and drug-drug interactions.1.The molecular genetic basis for variation in the activity of the four major drug metabolizing cytochrome P450(CYP) enzymes CYP2D6, CYP2Cl9, CYP1A2 and CYP3A4 will be explored. DNA based genotyping techniques will be developed as tools to predict the metabolic capacity in large populations and in clinical studies in patients. Different variant alleles will be characterized in expression systems. Probe drugs for the individual CYPs will be developed and evaluated in male and female subjects from different ethnic populations.2. The contribution of different CYPs for the metabolism of mianserin and clozapine will be studied in human liver tissue in vitro. The possible relationship between aberrant metabolic capacity and the risk to develop agranulocytosis during treatment with mianserin and clozapine will be evaluated. Patients who have developed this adverse effect will be identified and tested for metabolic capacity using probe drugs (caffeine for CYP1A2) or genotyping (for CYP2D6). 3. The disposition of nortriptyline and fluvoxamine will be studied in healthy volunteers with different drug metabolic phenotypes and genotypes. This will elucidate the contribution of the phenotype as assessed by probe drugs or the genotype (CYP2D6) on disposition and pharmacological effects of the drug. Using this approach, the importance of the duplicated/amplified CYP2D6 gene and that of other allelic variants found in European and Oriental populations will be elucidated. 4. The importance and predictive value of different CYP2D6 genotypes for the steady-state plasma levels and clinical effects (therapeutic effect/concentration dependent side effects) of antidepressants (nortriptyline) and neuroleptics perphenazine, zuclopenthixol, thioridazine, haloperidol) will be studied in patients. 5. Drug interactions at the level of specific CYPs will be studied in healthy volunteers and in patients. 6. Therapeutic drug monitoring data for antidepressant drugs and neuroleptics from the collaborating, countries will be analyzed using the population kinetic approach. This will provide data on pharmacokinetic variability, concentration-dependent kinetics, drug-drug interactions, influence of age, weight, gender etc, as well as interpopulation differences in psychotropic drug elimination. Dziedzina nauki natural sciencesbiological sciencesmolecular biologymolecular geneticsmedical and health sciencesclinical medicinepsychiatrynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesbasic medicinepharmacology and pharmacyadverse drug reactionsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Program(-y) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Temat(-y) 1.1 - Pharmacotoxicology Zaproszenie do składania wniosków Data not available System finansowania CSC - Cost-sharing contracts Koordynator Karolinska Institute Wkład UE Brak danych Adres HUDDINGE HOSPITAL 141 86 HUDDINGE Szwecja Zobacz na mapie Koszt całkowity Brak danych Uczestnicy (2) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko Universidad de Extremadura Hiszpania Wkład UE Brak danych Adres 06071 BADAJOZ Zobacz na mapie Koszt całkowity Brak danych Università degli Studi di Messina Włochy Wkład UE Brak danych Adres Piazza XX Settembre 4 98122 Messina Zobacz na mapie Koszt całkowity Brak danych
