Dicloxacillin-warfarin drug-drug interaction-A register-based study and in vitro investigations in 3D spheroid primary human hepatocytes

Br J Clin Pharmacol. 2023 Aug;89(8):2614-2624. doi: 10.1111/bcp.15738. Epub 2023 Apr 26.

Abstract

Aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: CYP; INR monitoring; anticoagulant; drug-drug interactions; induction; primary human hepatocytes; warfarin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticoagulants / adverse effects
  • Cytochrome P-450 Enzyme System / genetics
  • Dicloxacillin* / pharmacology
  • Drug Interactions
  • Floxacillin / pharmacology
  • Hepatocytes
  • Humans
  • International Normalized Ratio
  • Warfarin* / adverse effects

Substances

  • Warfarin
  • Dicloxacillin
  • Anticoagulants
  • Floxacillin
  • Cytochrome P-450 Enzyme System