Effect of CYP2C9 gene polymorphism on losartan dosage regimen in patients with I-II degree arterial hypertension

Background. Arterial hypertension (AH) occupies a leading position among cardiovascular diseases, determining the prognosis of morbidity and mortality among the population in the Russian Federation. Losartan is the first drug from the group of angiotensin II receptor antagonists, still frequently prescribed in the treatment of AH, often as monotherapy, which often determines the low efficacy of pharmacotherapy for AH. On the one hand, this is attributable to the losartan pharmacodynamics, on the other, from the point of view of pharmacogenetics, the efficacy of losartan can be influenced by the CYP2C9 gene polymorphisms, which affect the activity of the cytochrome P-450 isoenzyme 2C9 (CYP2C9), predetermining the pharmacological response. Objective. Evaluation of the effect of CYP2C9 gene polymorphism on the losartan dosage regimen in patients with I-II degree AH. Methods. The study included 81 patients - 46 (56.8%) men and 35 (43.2%) women with I - II degree AH aged 24 to 74 years, the mean age was 48.83±11.76 years. The study was conducted over a period of 12 weeks. At the first stage, 24-hour blood pressure monitoring and genotyping for CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910) allelic variants were performed by PCR-RFLP. Depending on the results of CYP2C9 genotyping, the patients were divided into two groups, compared with each other; the first group (n=55 [67.9%]) - carriers of the «wild» type CYP2C9*1/*1 and the second - (n=26 [32.1%]) - homo- and heterozygous carriers of CYP2C9*2 and CYP2C9*3 allelic variants. Then a course of losartan at a dose of25-50 mg/day was prescribed. At sche-duled visits (2, 4 and 8 weeks), blood pressure was monitored and, if necessary, therapy was corrected. At the second stage, after 12 weeks of follow-up, the effectiveness of therapy as well as the dose of losartan, was assessed in groups with different CYP2C9 genotypes. Results. Comparative analysis of losartan doses showed that carriage of CYP2C9*2 and CYP2C9*3 polymorphic alleles is associated with an increased chance of increasing the dose of losartan: OR=7.00 (95% CI: 2.225-22.018), P=0.001. It should be noted that the dose of losartan at the beginning of the study was significantly higher in individuals with the CYP2C9*1/*1 genotype (P=0.001); however, at the end of the study, no significant difference in doses between patients with different genotypes was found (P=0.414). Conclusion. Carriage of CYP2C9*2 and CYP2C9*3 polymorphic alleles («slow» alleles) is associated with an increase in the dose of losartan, in contrast to that in patients with the CYP2C9*1 /*1 genotype.

arterial hypertension, losartan, CYP2C9 gene polymorphism, pharmacogenetic testing