Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users

Abstract

Aim: We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: P‐glycoprotein transporter; antibiotics; direct oral anticoagulants; drug–drug interactions; stroke; systemic embolism.

FIGURE 1

An overview of the clinical study design. D, day; PK, pharmacokinetic.

FIGURE 2

Mean plasma concentration–time curve for dabigatran and the prodrug dabigatran etexilate after 10 and 28 days of dicloxacillin treatment in 10 healthy adults. Both curves show signs of induction of P‐gp.

FIGURE 3

Dicloxacillin increases expression of P‐gp (ABCB1) in LS174T cells. In 3D spheroid of primary human hepatocytes (PHH), both dicloxacillin and flucloxacillin increased the expression of P‐gp (ABCB1). In LS174T cells, n = 3 experiments are represented as mean values of triplicate (experiment 1) and duplicate (experiment 2 and 3) pools with duplicate technical replications. In 3D spheroid PHH, n = 3 donors for mRNA and 1 donor for protein are each represented as mean values of technical replicates. P‐gp, P‐glycoprotein.

FIGURE 4

Kaplan–Meier plot from 5–20 days risk of stroke/systemic embolism in patients taking direct oral anticoagulants cotreated with (A) dicloxacillin or phenoxymethylpenicillin or (B) flucloxacillin or amoxicillin.