engleski

CYP2C9 genetic polymorphism and warfarin therapeutic dose predicting by multiple linear regression model

Warfarin is an anticoagulant drug, whose dosage is carefully titrated to avoid the risk of serious side effect like life threatening bleeding. This risk exists at least in part due to genetic polymorphism in CYP2C9 - major enzyme of warfarin metabolism. Besides wild type allele CYP2C9*1, most common mutant alleles CYP2C9*2 and CYP2C9*3, code for enzymes with only 16-20% and 5% of total wild type activity, respectively. Three types of metabolic phenotype can be derived from genotype information (Poor metabolizer - PM, with both alleles mutant, Intermediate metabolizer - IM, with one mutated allele, and Extensive metabolizer, with both wild type alleles). The aim of the study was to find multiple regression model that could be used for dose prediction and to assess the importance of CYP2C9 genotyping in patients receiving warfarin anticoagulant therapy. We genotyped 181 patients (56.4% males, mean age 62) with PCR-RFLP method, who were receiving warfarin in doses needed for maintaining prothrombin time value within INR range 1.5-2.5. Other factors like gender, age, influence of other used drugs and the influence of different diagnoses were also included in the model assessment. Those factors showed to be of no importance for the model. Best multiple linear regression model showed to be a model which estimate optimal warfarin dose from standard dose at the beginning of therapy, patient's EM and PM phenotype, and the ratio of target INR value/INR derived 72 hours after therapy initiation. Within +/- 1mg deviation, this model is able to predict drug dose for about 76% of patients. In this model, IM phenotype contributes for 6%, and PM phenotype for 9% decrement of standard dose. This study confirmed that compared to 1/1 genotype, CYP2C9 impairment significantly decreases optimal warfarin therapy maintenance dose: 2/2 genotype decreases dose to 66%, and genotype 3/3 to 33% (P=0.025). IM phenotype decreases the dose to 88% (P=0.008), and PM to only 55%. Probability that CYP2C9*3 allele carriers will take doses smaller than 3mg is four times higher than non carriers (OR=4.14 ; 95%CI: 1.7-10.3). CYP2C9 allele, genotype and phenotype distribution in healthy population is concordant to other authors: 11.8% CYP2C9*2 alleles and 4.0% CYP2C9*3 alleles, genotype 1/1 (68.8%), 1/2 (22.6%), 1/3 (8.1 %), 2/2 (0.5%), and genotype 2/3 and 3/3 (0.0%). Study conclusion is that information derived from CYP2C9 genotyping can indicate to increased risk of warfarin therapy side effects, and that the use of proposed regression

CYP2C9 genotyping; warfarin; therapy side effects; linear regression model

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