Drug metabolism is one of the major determinants of variable drug action in man. Approximately 40 percent of human cytochrome P450 (CYP)-dependent drug metabolism is carried out by polymorphic enzymes exhibiting large genetically determined interindividual and interethnic variability in metabolic capacity due to the presence of allelic variants causing abolished, qualitatively or quantitatively altered, or enhanced enzyme activity. Such differences in drug metabolism may result in inadequate drug response in case of ultrarapid metabolism due to, e.g. gene duplication or multiduplication, or serious adverse effects in case of decreased metabolism due to defective alleles. The overall aim of the present application is to study the molecular genetic and enzymatic basis of interindividual and interethnic differences in drug metabolism catalysed by cytochrome P450 enzymes, and to evaluate the implications of such variability for the pharmacokinetics and clinical effects of important drugs in different ethnic groups. Special effort is placed on development and evaluation of genotyping and phenotyping methods for prediction of enzyme activity, and consequently, the pharmacokinetics and clinical effects of model drugs. The knowledge acquired will constitute a basis for individualised drug dosage, allowing more efficient and safer drug treatment, both for individual patients and different populations, taking the interethnic aspects into account. The project applies molecular genetic analysis of cytochrome P450 genes (CYP 1B1, 2A6, and 3A4) for detection of new allelic variants, analysis of the functional consequences of new and earlier identified mutations for drug metabolism in in vitro expression systems, development of phenotyping methods for assessment of enzyme activity in vivo in man, and evaluation of the genotype-phenotype relationships in different ethnic groups. The clinical implications of interindividual and interethnic variability, as determined by geno- and phenotyping, for the pharmacokinetics and clinical effects of model drugs metabolised by the polymorphic P450s are studied in healthy volunteers and patients treated with therapeutic doses of the drugs. The project combines molecular pharmacogenetic and clinical pharmacological assessment of drug metabolism and drug action in man.
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