Genetic polymorphism of Cytochrome P450 isoenzymes
Genetički polimorfizam izoenzima Citohroma P450
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The aim of this review is to explain genetic basis of interindividual variability in cytochrome P450 (CYP450) dependent drug metabolism and highlight the clinical significance of different polymorphisms. Nearly all CYP450 isoenzymes involved in drug metabolism have been shown to be polymorphic, although some of them are functionally well conserved (CYP2E1 and CYP3A4) in comparison with others (CYP2D6, CYP2C19 and CYP2C9). Genetic variability in drug metabolizing enzymes can be assessed at the level of phenotype (by investigating enzyme level/activity) and/or genotype (by determining which alleles are present). Polymorphism divides a population into at least two phenotypes: individuals with deficient metabolism are termed „poor metabolizers” (PM), as compared to normal or „extensive metabolizers” (EM). In case of CYP2D6, „ultrarapide metabolizers” (UM) with extremely high enzyme activity, have also been identified. The clinical significance of particular polymorphism depends on the impo...rtance of metabolic pathway under polymorphic control, therapeutic index (TI) of a drug and its active metabolites, and incidence of the polymorphism in a particular population. Therapeutic consequences vary from increased risk of adverse reactions in PM, to therapeutic failure at standard drug doses in UM (if drug metabolites are inactive). Drug dosage, especially for narrow TI drugs, should be adjusted to the metabolic capacity of a patient , by phenotyping/genotyping prior to drug therapy.
Keywords:CYP450 isoenzymes / drug metabolism / genetic polymorphism / clinical significance / izoenzimi CYP450 / metabolizam lekova / genetički polimorfizam / klinički značaj
Source:Arhiv za farmaciju, 2004, 54, 1-2, 61-76
- Savez farmaceutskih udruženja Srbije, Beograd