Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark.
SIGNATOPE GmbH, Reutlingen, Germany.
Br J Clin Pharmacol. 2023 Aug;89(8):2614-2624. doi: 10.1111/bcp.15738. Epub 2023 Apr 26.
Dicloxacillin is used to treat staphylococcal infections and we have previously shown that dicloxacillin is an inducer of cytochrome P450 enzymes (CYPs). Here, we employed a translational approach to investigate the effect of a treatment with dicloxacillin on warfarin efficacy in Danish registries. Furthermore, we assessed dicloxacillin as an inducer of CYPs in vitro.
We conducted a register-based study and analysed international normalized ratio (INR) levels in chronic warfarin users before and after short- and long-term use of dicloxacillin (n = 1023) and flucloxacillin (n = 123). Induction of CYPs were investigated in a novel liver model of 3D spheroid primary human hepatocytes at the level of mRNA, and protein and enzyme activity.
Short- and long-term dicloxacillin treatments decreased INR levels by -0.65 (95% confidence interval [CI]: -0.57 to -0.74) and -0.76 (95% CI: -0.50 to -1.02), respectively. More than 90% of individuals experienced subtherapeutic INR levels (below 2) after long-term dicloxacillin treatment. Flucloxacillin decreased INR levels by -0.37 (95% CI: -0.14 to -0.60). In 3D spheroid primary human hepatocytes, the maximal induction of CYP3A4 mRNA, protein and enzyme activity by dicloxacillin were 4.9-, 2.9- and 2.4-fold, respectively. Dicloxacillin also induced CYP2C9 mRNA by 1.7-fold.
Dicloxacillin induces CYPs and reduces the clinical efficacy of warfarin in patients. This effect is substantially exacerbated during long-term treatment with dicloxacillin. The in vitro results corroborated this drug-drug interaction and correlated to the clinical findings. Caution is warranted for warfarin patients that initiate dicloxacillin or flucloxacillin, especially for a long-term treatment of endocarditis.
双氯西林用于治疗葡萄球菌感染，我们之前已经表明，双氯西林是细胞色素 P450 酶（CYPs）的诱导剂。在这里，我们采用一种转化方法来研究双氯西林治疗对丹麦注册处华法林疗效的影响。此外，我们评估了双氯西林在体外对 CYP 的诱导作用。
我们进行了一项基于登记的研究，分析了慢性华法林使用者在短期和长期使用双氯西林（n=1023）和氟氯西林（n=123）前后的国际标准化比值（INR）水平。在新型三维球体原代人肝细胞肝脏模型中，从 mRNA、蛋白和酶活性水平研究了 CYP 的诱导作用。
短期和长期双氯西林治疗分别使 INR 水平降低了-0.65（95%置信区间 [CI]：-0.57 至 -0.74）和-0.76（95% CI：-0.50 至 -1.02）。超过 90%的个体在长期双氯西林治疗后经历了低于治疗范围的 INR 水平（低于 2）。氟氯西林使 INR 水平降低了-0.37（95% CI：-0.14 至 -0.60）。在 3D 球体原代人肝细胞中，双氯西林对 CYP3A4 mRNA、蛋白和酶活性的最大诱导作用分别为 4.9 倍、2.9 倍和 2.4 倍。双氯西林还使 CYP2C9 mRNA 诱导了 1.7 倍。
双氯西林诱导 CYP，并降低患者华法林的临床疗效。在长期使用双氯西林治疗期间，这种作用会显著加剧。体外结果证实了这种药物相互作用，并与临床发现相关。对于开始使用双氯西林或氟氯西林的华法林患者，特别是长期治疗心内膜炎的患者，应谨慎。
