Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands.
Br J Clin Pharmacol. 2024 Dec;90(12):3252-3262. doi: 10.1111/bcp.16190. Epub 2024 Aug 19.
We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism.
In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P-glycoprotein (P-gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P-gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators.
Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10 days of 0.67 (95% confidence interval [CI]: 0.42-1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39-1.4), suggesting reduced oral absorption via increased P-gp expression. In vitro, dicloxacillin raised P-gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72-1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51-1.5).
Dicloxacillin increases expression of intestinal P-gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug-drug interaction between dicloxacillin/flucloxacillin and DOACs.
评估双氯西林/氟氯西林是否降低直接口服抗凝剂（DOACs）的治疗效果，以及潜在的分子机制。
在一项随机、交叉研究中，我们评估了双氯西林在 10 天和 28 天治疗期间是否通过 P 糖蛋白（P-gp）减少药物的口服吸收。为了研究双氯西林/氟氯西林对 LS174T 细胞和原代人肝细胞 3D 球体中肠和肝内 P-gp 表达的影响，我们使用了这些细胞。最后，我们使用丹麦全国卫生登记处和英国临床实践研究数据链接，以评估 DOAC 使用者暴露于双氯西林/氟氯西林后发生中风和全身性栓塞的风险的危害比（HRs），使用苯氧甲基青霉素和阿莫西林作为活性对照。
双氯西林使达比加群的 AUC 在 10 天时的几何平均比为 0.67（95%置信区间[CI]：0.42-1.1），在 28 天时的几何平均比为 0.72（95%CI：0.39-1.4），表明通过增加 P-gp 表达来减少口服吸收。在体外，双氯西林增加了肠和肝细胞中的 P-gp 表达，而氟氯西林仅影响肝细胞。在药物流行病学研究中，双氯西林和氟氯西林与中风/全身性栓塞风险增加无关（双氯西林与苯氧甲基青霉素 HR：0.93，95%CI：0.72-1.2；氟氯西林与阿莫西林 HR：0.89，95%CI：0.51-1.5）。
双氯西林增加了肠 P-gp 的表达，导致达比加群的口服吸收减少。然而，在 DOAC 使用者中，同时使用双氯西林/氟氯西林与中风和全身性栓塞无关，这表明双氯西林/氟氯西林与 DOACs 之间的药物相互作用没有临床影响。
