engleski

Association of warfarin dosing with cytochrome P450 - CYP2C9 genetic polymorphism

Warfarin is a racemic drug with the predominant anticoagulant effect expressed by S–enantiomer and is a therapeutic of choice for anticoagulant drug therapy maintenance. Drug dosage is sometimes complicated by unpredictable dose response that may be in part due to genetically determined differences in metabolic capacity. S-warfarin is hydroxylated to its inactive metabolite primarily by polymorphic cytochrome P450 enzyme – CYP2C9. Besides its wild type allele - CYP2C9*1, there are two mutant alleles CYP2C9*2 (Cys144Arg) and CYP2C9*3 (Leu359Ile) that in homozygous state express enzymes of very low activity (only 16-20% and 5% of total wild type activity, respectively). We investigated the association of CYP2C9 genetic polymorphism with differences in drug dosage among 71 patients (51% males, mean age 59.7 ; SD=14.8), receiving warfarin therapy for at least 2 weeks after individual dose optimization. RFLP genotyping for CYP2C9*1, 2* and 3* alleles was performed by using Ava II, Nsi I, and Kpn I restriction endonucleases (method by Yasar U. et al., 1999). Study results showed that mean daily warfarin dose for wild type homozygote patients, (5.2mg ; SD=1.9) appeared to be significantly higher (p=0.036) compared to mean daily dose for patients with at least one allele mutated (4.3mg ; SD=1.6). Patients were also divided into groups according to median daily dose (DD) of warfarin - DD<5.0mg (44 patients) and DD>5.0mg (27 patients). In DD<5.0mg group we found 71% wild type (1*), and 29% mutated (2* and 3*) alleles. These allelic frequencies were significantly lower (p=0.022) than in DD>5.0mg group (87% wild type (1*), and 13% mutated (2* and 3*) alleles). Genotype frequencies between DD<5.0mg group (45% homozygous wild type, 50% heterozygous and 5% mutant homozygous) and DD>5.0mg group (74% homozygous wild type, 26% heterozygous and none mutant homozygous) also differed significantly (p=0.049). Results of our preliminary investigation are concordant to other author findings and suggest that CYP2C9 defective alleles are related to warfarin dosage, and therefore could be of importance in predicting and optimizing anticoagulant drug therapy. In order to confirm these findings, further study remains to be done.

Warfarin; CYP2C9; anticoagulant drug therapy

nije evidentirano