Author/Editor     Dolžan, Vita
Title     Genetic polymorphisms and drug metabolism
Translated title     Genetski polimorfizmi in presnova zdravil
Type     članek
Source     Zdrav Vestn
Vol. and No.     Letnik 76, št. Suppl 2
Publication year     2007
Volume     str. II-5-12
ISSN     1318-0347
Language     eng
Abstract     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 determinantin drug response. Pharmacogenetics aims to identifygenetic sources of variability in response to drugs by studyinggenetic variations caffecting drug metabolizing enzymes, transporters and drug targets thus causing interinclividual 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 Il enzymes: UDP glucuronosyltransferases (UGTs), N-acetyl-transferries (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. (Abstract truncated at 2000 characters)
Summary     Izhodišča Različni bolniki se na predpisani odmerek zdravila ne odzovejo enako. Na interindividualne razlike v hitrosti in učinkovitosti presnove in delovanja velikega števila zdravil pomembno vplivajo tudi genetski dejavniki. Farmakogenetika preučuje vpliv genetske variabilnosti encimov, ki presnavljajo zdravila, prenašalcev (transporterjev) in tarčnih molekul, na katere zdravila delujejo, na presnovo zdravil, učinkovitost farmakoterapije in neželene učinke zdravljenja. Izmed genetskih dejavnikov je najpomembnejša genetska variabilnost encimov, ki presnavljajo zdravila, saj vpliva na učinkovitost več kot 30% zdravil. Presnova zdravil v telesu poteka s pomočjo specifičnih encimskih sistemov pretežno v dveh stopnjah. V prvi stopnji (faza I) nastane bolj elektrofilen, aktiviran presnovek, ki v naslednji stopnji (faza II) vstopi v reakcije konjugacije, ki jih katalizirajo UDP-glukuronoziltransferaze (UGT), N-acetil-transferaze (NAT), glutation S-transferaze (GST) in drugi encimi, s čimer se poveča vodotopnost molekule. Za presnovo zdravil so v fazi I najbolj pomembni citokromi P450 iz treh družin, CYP1, CYP2 in CYP3, ki jih večinoma kodirajo polimorfni geni. Genetski polimorfizem pomeni, da sta v populaciji prisotna najmanj dva alela nekega gena, pri čemer je frekvenca manj pogostega alela vsaj 1%. Po nekaterih ocenah bi genotipizacija lahko zmanjšala stroške zdravljenja, prispevala k varnejšemu zdravljenju pri 15-25% vseh klinično uporabljanih zdravil in zmanjšala pogostnost neželenih učinkov za 10-20%. Čeprav postopki genotipizacije postajajo vse hitrejši, enostavnejši in cenejši, se farmakogenetsko testiranje v klinični praksi še ne uporablja. (Izvleček skrajšan pri 2000 znakih)
Descriptors     PHARMACOGENETICS
POLYMORPHISM (GENETICS)
CYTOCHROME P-450
GENOTYPE
METABOLIC DETOXICATION, DRUG