Department of Pharmacy.
Department of Pharmacology, Faculty of Medicine, UPV/EHU, Spain.
Int J Surg. 2023 Dec 1;109(12):3861-3871. doi: 10.1097/JS9.0000000000000673.
Due to the high individual variability of anticoagulant warfarin, this study aimed to investigate the effects of vitamin K concentration and gut microbiota on individual variability of warfarin in 246 cardiac surgery patients.
The pharmacokinetics and pharmacodynamics (PKPD) model predicted international normalized ratio (INR) and warfarin concentration. Serum and fecal samples were collected to detect warfarin and vitamin K [VK1 and menaquinone-4 (MK4)] concentrations and gut microbiota diversity, respectively. In addition, the patient's medical records were reviewed for demographic characteristics, drug history, and CYP2C9, VKORC1, and CYP4F2 genotypes.
The PKPD model predicted ideal values of 62.7% for S-warfarin, 70.4% for R-warfarin, and 76.4% for INR. The normal VK1 level was 1.34±1.12 nmol/ml (95% CI: 0.33-4.08 nmol/ml), and the normal MK4 level was 0.22±0.18 nmol/ml (95% CI: 0.07-0.63 nmol/ml). The MK4 to total vitamin K ratio was 16.5±9.8% (95% CI: 4.3-41.5%). The S-warfarin concentration of producing 50% of maximum anticoagulation and the half-life of prothrombin complex activity tended to increase with vitamin K. Further, Prevotella and Eubacterium of gut microbiota identified as the main bacteria associated with individual variability of warfarin. The results suggest that an increase in vitamin K concentration can decrease anticoagulation, and gut microbiota may influence warfarin anticoagulation through vitamin K2 synthesis.
This study highlights the importance of considering vitamin K concentration and gut microbiota when prescribing warfarin. The findings may have significant implications for the personalized use of warfarin. Further research is needed to understand better the role of vitamin K and gut microbiota in warfarin anticoagulation.
由于抗凝剂华法林的个体变异性很高，本研究旨在调查维生素 K 浓度和肠道微生物群对 246 例心脏手术患者华法林个体变异性的影响。
药代动力学和药效学（PKPD）模型预测国际标准化比值（INR）和华法林浓度。分别收集血清和粪便样本，以检测华法林和维生素 K[VK1 和甲萘醌-4（MK4）]浓度以及肠道微生物群多样性。此外，还回顾了患者的人口统计学特征、药物史以及 CYP2C9、VKORC1 和 CYP4F2 基因型。
PKPD 模型预测 S-华法林、R-华法林和 INR 的理想值分别为 62.7%、70.4%和 76.4%。正常 VK1 水平为 1.34±1.12 nmol/ml（95%CI：0.33-4.08 nmol/ml），正常 MK4 水平为 0.22±0.18 nmol/ml（95%CI：0.07-0.63 nmol/ml）。MK4 与总维生素 K 的比值为 16.5±9.8%（95%CI：4.3-41.5%）。产生最大抗凝作用的 50%的 S-华法林浓度和凝血酶原复合物活性的半衰期趋于随维生素 K 增加而增加。此外，肠道微生物群中的普雷沃氏菌属和真杆菌属被确定为与华法林个体变异性相关的主要细菌。结果表明，维生素 K 浓度的增加可以降低抗凝作用，而肠道微生物群可能通过维生素 K2 的合成影响华法林的抗凝作用。
本研究强调了在开华法林处方时考虑维生素 K 浓度和肠道微生物群的重要性。研究结果对华法林个体化应用具有重要意义。需要进一步研究以更好地了解维生素 K 和肠道微生物群在华法林抗凝中的作用。
