CYP2C9基因分型可预测厄贝沙坦的血压反应：瑞典厄贝沙坦与阿替洛尔治疗左心室肥厚比较研究（SILVHIA）试验结果

The CYP2C9 genotype predicts the blood pressure response to irbesartan: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial.

作者信息

Hallberg Pär, Karlsson Julia, Kurland Lisa, Lind Lars, Kahan Thomas, Malmqvist Karin, Ohman K Peter, Nyström Fredrik, Melhus Håkan

机构信息

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

出版信息

J Hypertens. 2002 Oct;20(10):2089-93. doi: 10.1097/00004872-200210000-00030.

DOI:10.1097/00004872-200210000-00030

PMID:12359989

Abstract

BACKGROUND

The cytochrome P450 CYP2C9 enzyme (CYP2C9) metabolizes many clinically important drugs, for example, phenytoin, warfarin and the angiotensin II type 1 (AT(1)) receptor antagonists, losartan and irbesartan. Single nucleotide polymorphisms in the CYP2C9 gene result in the expression of three important variants, CYP2C91(wild-type), CYP2C92 and CYP2C9*3, the last two exhibiting reduced catalytic activity compared with the wild-type. The CYP2C9 genotype is known to determine sensitivity to and dose requirements for both warfarin and phenytoin, and also the rate of metabolism of losartan. However, its influence on clinical response to treatment with the AT(1) receptor antagonist, irbesartan, has not been investigated.

OBJECTIVE

To determine whether the CYP2C9genotype influences the blood pressure-decreasing response to antihypertensive treatment with irbesartan.

DESIGN AND METHODS

One hundred and two patients with essential hypertension and left ventricular hypertrophy were allocated randomly to groups to receive double-blind treatment with either irbesartan (n = 49) or the beta(1)-adrenergic receptor blocker, atenolol ( n= 53). Blood pressure was measured before and after 12 weeks of treatment. genotyping was performed using solid-phase minisequencing.

RESULTS

The diastolic blood pressure (DBP) response differed in relation to the CYP2C9 genotype in patients given irbesartan: the reduction in patients with genotype CYP2C91/CYP2C91 (n = 33) was 7.5% and that with CYP2C91/CYP2C92 (n = 12) was 14.4% ( P= 0.036). A similar trend was seen for systolic blood pressure. In contrast, no relation was seen between the CYP2C9 genotype and blood pressure response to atenolol, a drug not metabolized via CYP2C9.

CONCLUSIONS

The CYP2C9 genotype seems to predict the DBP response to irbesartan, but not to atenolol, in patients with essential hypertension.

摘要

背景

细胞色素P450 CYP2C9酶（CYP2C9）可代谢多种临床上重要的药物，例如苯妥英、华法林以及1型血管紧张素II（AT(1)）受体拮抗剂氯沙坦和厄贝沙坦。CYP2C9基因中的单核苷酸多态性导致三种重要变异体的表达，即CYP2C91（野生型）、CYP2C92和CYP2C9*3，后两者与野生型相比催化活性降低。已知CYP2C9基因型可决定对华法林和苯妥英的敏感性及剂量需求，以及氯沙坦的代谢速率。然而，其对AT(1)受体拮抗剂厄贝沙坦治疗临床反应的影响尚未得到研究。

目的

确定CYP2C9基因型是否影响厄贝沙坦降压治疗的血压下降反应。

设计与方法

102例原发性高血压合并左心室肥厚患者被随机分组，分别接受厄贝沙坦（n = 49）或β(1)肾上腺素能受体阻滞剂阿替洛尔（n = 53）的双盲治疗。在治疗12周前后测量血压。采用固相微测序法进行基因分型。

结果

接受厄贝沙坦治疗的患者中，舒张压（DBP）反应因CYP2C9基因型而异：CYP2C91/CYP2C91基因型患者（n = 33）的血压降低7.5%，CYP2C91/CYP2C92基因型患者（n = 12）的血压降低14.4%（P = 0.036）。收缩压也呈现类似趋势。相比之下，CYP2C9基因型与阿替洛尔（一种不通过CYP2C9代谢的药物）的血压反应之间无关联。