engleski

Polymorphism of CYP2D6 and CYP2C9 in predicting drug metabolism phenotype

Adverse drug reactions have recently been reported to occur as the fourth to sixth cause of death in hospital patients, accounting for one of 15 (6.7%) hospital admissions, whereby one of 300 (0.3%) such reactions has a fatal outcome. Adverse drug reaction can be induced by some transient causes such as drug metabolizing enzyme inhibition or induction, or by some permanent cause such as genetic mutation or gene deletion-polymorphism. CYP2D6 and CYP2C9 are cytochrome P450 isoenzymes involved in the metabolism of most drugs, that are drugs of choice for the treatment of psychotic symptoms and thromboembolic episodes, respectively. A functional polymorphism of CYP2D6 is connected to at least six mutant alleles (null alleles *3, *4, *5, *6, *7 and *8) encoding for inactive enzymatic molecules, and that of CYP2C9 to two mutant alleles (alleles *2 and *3) encoding for CYP2C9 enzymes with a potentially different catalytic activity. The aim of the study was to assess the association between CYP2D6 polymorphism and side effects in psychiatric patients suffering from schizophrenia (n=87) on long term therapy with psychoactive drugs (ƒŽ5 years), and to evaluate the association between CYP2C9 polymorphism and warfarin dose in the development of thromboembolism (n=54). The CYP2D6 genotype was determined using allele-specific multiplex PCR and CYP2C9 by PCR-RFLP. Results obtained in the study of CYP2D6 polymorphism indicated a significant difference in allele (p=0.002) and genotype (p=0.029) distribution between patients with (n=37) and without (n=47) side effects, with a considerably higher frequency of heterozygous (34.2%) and homozygous (13.2%) 2D6*4 allele in former. The odds ratio of 2.626 for 2D6*4 and 5.333 for 2D6*6 allele suggested a significant association of these alleles and side effects in schizophrenic patients on long-term therapy. The prevalence of poor and intermediate predicted phenotype was significantly higher in the side effect group compared to the non-side effect group (p=0.002). The odds ratio of 7.075 (2.010 to 24.908) suggested a strong association between PM phenotype and side effects. In thromboembolism patients, the distribution of CYP2C9 alleles *2 and *3 was 12.7% and 2.8%, respectively. In this group, beside the wild type the 1/2, 1/3, 2/3, and 2/2 genotypes were found in 41.5%, 3.8%, 1.9%, and 1.9% of the subjects, respectively, which was not significantly different from healthy subjects (n=51 ; p=0.128). The group of throbmoembolism patients were divided into two subgroups according to the warfarin dose required for optimal therapeutic effect (ƒŹ4.5mg and ƒŽ4.5mg warfarin/day). Although the genotype and allele distribution differed between these two subgroups, the difference did not reach significance (genotype p = 0.196, allele p=0.069). These preliminary results suggest a significant association of CYP2D6 polymorphism with side effects and association of CYP2C9 polymorphism and warfarin dose, underlying the importance of pre-treatment genotyping, to identify the subjects prone to adverse drug reaction.

CYP2D6; CYP2C9; drug metabolism phenotyping

nije evidentirano