Genetic polymorphisms and drug metabolism
Keywords:
pharmacogenetics, polymorphism, drug metabolism, cytochromes P450, genotypingAbstract
Background: It is estimated that genetic factors account for 15–30 % of variability in drug response, however for some drugs this may be the major determinant in drug response. Pharmacogenetics aims to identify genetic sources of variability in response to drugs by studying genetic variations affecting drug metabolizing enzymes, transporters and drug targets thus causing interindividual variability in drug levels (pharmacokinetics), drug response (pharmacodynamics) and side effects. Extensive information on genetic variability in drug metabolizing enzymes, transporters and targets is available from public databases. Drugs are metabolized in two phases. In Phase I drug is metabolically activated to reactive electrophilic form, mostly by cytochromes P450 (CYPs), to be conjugated to some endogenous compound by Phase II enzymes: UDP-glucuronosyltransferases (UGTs), N-acetyl-transferases (NATs), glutathione S-transferases (GSTs), or others. Genetic polymorphism of many enzymes involved in this process leads to inter-individual variations in metabolism and pharmacokinetics of drugs and could therefore influence drug response. Genetic polymorphism is the occurrence of two or more alleles at a given locus of which the rare allele has a frequency of at least 1 % or more in a given population. The understanding of a patient’s genotype and its corresponding effect on drug response could help distinguish between responders and non-responders of a specific drug treatment and help to choose the most effective drug and optimal dose. A large number of different methodologies have been developed for genotyping, however at present predictive genotyping for drug metabolizing enzymes does not occur routinely in the clinical practice.
Conclusions: There is increasing evidence that genotyping for polymorphic drug metabolizing enzymes, in particular CYPs has potential to improve drug therapy and achieve higher response rates and reduced adverse effects. Open questions regarding the relevance of the knowledge of pharmacogenetic information for clinical end points and the cost-benefit aspects of pharmacogenetic based dosing need to be answered by prospective randomized clinical trials.
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