Department of Pharmacology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Khyber Pakhtunkhwa, Pakistan.
Institute of Pharmaceutical Sciences, Khyber Medical University, Peshawar 25100, Khyber Pakhtunkhwa, Pakistan.
Medicina (Kaunas). 2024 Oct 18;60(10):1712. doi: 10.3390/medicina60101712.
: Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. : The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. : The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. : It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding.
利伐沙班是一种直接作用的抗凝剂，用于预防房颤患者的中风。利伐沙班是 P-糖蛋白的底物，P-糖蛋白由 ABCB1 基因编码。利伐沙班也由 CYP3A5 基因代谢。因此，目前的研究是为了研究 ABCB1 和 CYP3A5 基因的多态性对利伐沙班血浆水平的影响，随后与治疗相关的出血事件（出血事件）的临床结果。
该研究对 66 名接受利伐沙班治疗的初发房颤患者进行了研究。在给药后 3 小时和 1 个月时采集利伐沙班的血样，以测量血浆水平。用 HPLC-UV 检测器测量利伐沙班的血药浓度。采用 Sanger 测序法检测靶向基因的多态性。在给予利伐沙班 3 小时和 1 个月后测量凝血参数。记录整个一个月的药物治疗过程中的出血事件频率。
ABCB1（rs2032582、rs1045642、rs1128503 和 rs4148738）和 CYP3A5（rs776746）的杂合和纯合突变基因型与野生型基因型相比，血浆浓度较低。ABCB1（rs2032582、rs1045642、rs1128503 和 rs4148738）和 CYP3A5（rs776746）基因多态性在杂合和纯合突变基因型与野生型基因型相比，对利伐沙班的血浆浓度有统计学显著影响。ABCB1 杂合变体和 CYP3A5 纯合变体的出血事件更多。
结论是，ABCB1（rs2032582、rs1045642、rs1128503 和 rs4148738）和 CYP3A5（rs776746）基因多态性对房颤患者第 3 天和治疗 1 个月后的利伐沙班血浆水平有显著影响。在 ABCB1（rs2032582、rs1045642 或 rs4148738）与 CYP3A5*1/*3 等位基因纯合变体的患者中观察到最低的血浆水平。ABCB1SNP 杂合变体和 CYP3A5SNP 纯合变体的出血事件更多。
