Chen Wenjun, Qian Jiafen, Fu Jinglan, Wu Tingting, Lv Meina, Jiang Shaojun, Zhang Jinhua
Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China.
College of Pharmacy, Fujian Medical University, Fuzhou, China.
Front Pharmacol. 2022 Mar 25;13:860237. doi: 10.3389/fphar.2022.860237. eCollection 2022.
The mechanism underlying large individual differences in the response to oral anticoagulants has not been fully clarified, and the influence of the intestinal microbiome on exogenous drug metabolism has gradually become an area of increased research interest. However, there has been no research into the influence of the gut microbiota on the pharmacokinetics of oral anticoagulants. Therefore, our study is the first to investigate the effect of the intestinal flora on oral anticoagulant metabolism and the associated mechanism. Antibiotics affected the diversity and abundance of the intestinal flora. Compared with the control group, the bioavailability of warfarin and rivaroxaban were significantly increased in the amoxicillin-treated group, whereas the bioavailability of dabigatran increased and subsequently decreased. Compared with the control group, the expression of P-glycoprotein (P-gp), CYP1A2, CYP2C9, CYP3A4, and nuclear receptor, PXR, were altered in the amoxicillin -treated groups. This trend was consistent with the pharmacokinetic results. Changes in the intestinal flora can affect the expression of liver drug enzymes and P-gp, as well as affect the transport and metabolism of oral anticoagulants (e.g., warfarin, dabigatracin, and rivaroxaban), leading to differences in the efficacy of oral anticoagulants. This study revealed a novel mechanism for influencing individual differences in the treatment efficacy of oral anticoagulants.
口服抗凝药反应存在巨大个体差异的潜在机制尚未完全阐明，肠道微生物群对外源性药物代谢的影响已逐渐成为一个研究兴趣日益增加的领域。然而，尚未有关于肠道微生物群对口服抗凝药药代动力学影响的研究。因此，我们的研究首次探讨了肠道菌群对口服抗凝药代谢的影响及其相关机制。抗生素影响了肠道菌群的多样性和丰度。与对照组相比，阿莫西林治疗组华法林和利伐沙班的生物利用度显著增加，而达比加群的生物利用度先增加后降低。与对照组相比，阿莫西林治疗组中P-糖蛋白（P-gp）、CYP1A2、CYP2C9、CYP3A4和核受体PXR的表达发生了改变。这一趋势与药代动力学结果一致。肠道菌群的变化可影响肝脏药物酶和P-gp的表达，还可影响口服抗凝药（如华法林、达比加群和利伐沙班）的转运和代谢，导致口服抗凝药疗效出现差异。本研究揭示了影响口服抗凝药治疗效果个体差异的新机制。
