PDF(Pubmed)
Abstract：
Background: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). Methods: A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and CES1 rs2244613, CES1 rs8192935 and ABCB1 rs4148738 SNP while on two different dabigatran doses (110 and 150 mg BID). Results: A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different CES1 rs2244613 and CES1 rs8192935 genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44-111) ng/mL in patients with the ABCB1 rs4148738 heterozygous CT genotype vs. 127 (85-147) ng/mL in the wild-type CC genotype vs. 110 (47-159) ng/mL in the mutant trait TT genotype (p = 0.048). In patients with the ABCB1 rs4148738 CT genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 (p = 0.042). Conclusions: ABCB1 rs4148738 CT heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.
摘要：
背景：达比加群etexilate是通过羧酸酯酶（CES）水解成达比加群的前药，并且是三磷酸腺苷结合盒亚家族B成员（ABCB）1基因编码的P-糖蛋白的底物。我们根据不同的CES1和ABCB1单核苷酸多态性（SNP）评估了房颤（AF）患者对达比加群的功能反应。方法：两个意大利中心共纳入100例服用达比加群的房颤患者。抽取静脉血样本进行基因测定,以及稀释的凝血酶时间（dTT）和药物血浆浓度的测量，在低谷和顶峰。主要目标是在两种不同的达比加群剂量（110和150mgBID）下，dTT值与CES1rs2244613，CES1rs8192935和ABCB1rs4148738SNP之间的关系。结果：共有43例患者接受110mg达比加群剂量，57例患者接受150mg剂量。不同CES1rs2244613和CES1rs8192935基因型的患者在波谷和峰值的DTT值没有差异，不管达比加群的剂量.在150毫克达比加群的患者中，在ABCB1rs4148738杂合CT基因型患者中，低谷的dTT值为77（44-111）ng/mL。127（85-147）ng/mL在野生型CC基因型与110(47-159)ng/mL的突变性状TT基因型(p=0.048)。在ABCB1rs4148738CT基因型患者中，dTT值低于中位数的OR为3.21，95％CI1.04-9.88（p=0.042）。结论：ABCB1rs4148738CT杂合子与接受较高剂量方案的患者达比加群在低谷的抗凝活性降低有关。
