Cumitini Luca, Renda Giulia, Giordano Mara, Rolla Roberta, Shail Tarek, Sacchetti Sara, Iezzi Lorena, Giacomini Luca, Zanotti Valentina, Auciello Raffaella, Angilletta Ilaria, Foglietta Melissa, Zucchelli Mirco, Antonucci Ivana, Stuppia Liborio, Gallina Sabina, Dianzani Umberto, Patti Giuseppe
Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.
Division of Cardiology, AOU Maggiore della Carità, 28100 Novara, Italy.
J Clin Med. 2024 Apr 26;13(9):2545. doi: 10.3390/jcm13092545.
: 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). : 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 , and SNP while on two different dabigatran doses (110 and 150 mg BID). : 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 and 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 heterozygous 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 ( = 0.048). In patients with the genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 ( = 0.042). : heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.
达比加群酯是一种前体药物，可被羧酸酯酶（CES）水解为达比加群，并且是由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。我们根据心房颤动（AF）患者中不同的CES1和ABCB1单核苷酸多态性（SNP）评估了对达比加群的功能反应。
两个意大利中心共纳入了100例连续服用达比加群的AF患者。采集静脉血样用于基因测定，以及在谷值和峰值时测量稀释凝血酶时间（dTT）和药物血浆浓度。主要目的是在两种不同的达比加群剂量（110和150mg，每日两次）下，dTT值与 、 和 SNP之间的关系。
共有43例患者服用110mg达比加群剂量，57例服用150mg。无论达比加群剂量如何，不同 和 基因型患者的谷值和峰值DTT值均无差异。在服用150mg达比加群的患者中， 杂合 基因型患者的谷值dTT值为77（44-111）ng/mL，野生型CC基因型患者为127（85-147）ng/mL，突变性状TT基因型患者为110（47-159）ng/mL（P = 0.048）。在 基因型患者中，谷值dTT值低于中位数的OR为3.21，95%CI为1.04-9.88（P = 0.042）。
在接受高剂量方案的患者中， 杂合子与达比加群在谷值时抗凝活性降低有关。
