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

Ditte B Iversen; Ann-Cathrine Dalgård Dunvald; Martin Thomsen Ernst; Shahab Abtahi; Patrick Souverein; Olaf Klungel; Glenn Brøde Jeppesen; Flemming Nielsen; Kim Brøsen; Helen S Hammer; Oliver Pötz; Per Damkier; Erkka Järvinen; Anton Pottegård; Tore B Stage

doi:10.1111/bcp.16190

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

Ditte B Iversen, Ann-Cathrine Dalgård Dunvald, Martin Thomsen Ernst, Shahab Abtahi, Patrick Souverein, Olaf Klungel, Glenn Brøde Jeppesen, Flemming Nielsen, Kim Brøsen, Helen S Hammer, Oliver Pötz, Per Damkier, Erkka Järvinen, Anton Pottegård, Tore B Stage^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	3252-3262
Number of pages	11
Journal	British Journal of Clinical Pharmacology
Volume	90
Issue number	12
Early online date	19 Aug 2024
DOIs	https://doi.org/10.1111/bcp.16190
Publication status	Published - Dec 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Funding

This work was supported by the Novo Nordisk Foundation (Grant number NNF19OC0058275 to T.B.S.) and the Lundbeck Foundation Fellowship (Grant number R307\u20132018\u20102980 to T.B.S.). Funding information

Funders	Funder number
Novo Nordisk Foundation	NNF19OC0058275
Lundbeck Foundation Fellowship	R307-2018-2980

Keywords

P-glycoprotein transporter
antibiotics
direct oral anticoagulants
drug–drug interactions
stroke
systemic embolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1111/bcp.16190Licence: CC BY-NC

Brit J Clinical Pharma - 2024 - Iversen - Dicloxacillin is an inducer of intestinal P‐glycoprotein but neitherFinal published version, 1.42 MBLicence: CC BY-NC

Cite this

Iversen, D. B., Dunvald, A.-C. D., Ernst, M. T., Abtahi, S., Souverein, P., Klungel, O., Jeppesen, G. B., Nielsen, F., Brøsen, K., Hammer, H. S., Pötz, O., Damkier, P., Järvinen, E., Pottegård, A., & Stage, T. B. (2024). 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. British Journal of Clinical Pharmacology, 90(12), 3252-3262. https://doi.org/10.1111/bcp.16190

@article{acf3930636974d8cac47960cad90c71f,

title = "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",

author = "Iversen, {Ditte B} and Dunvald, {Ann-Cathrine Dalg{\aa}rd} and Ernst, {Martin Thomsen} and Shahab Abtahi and Patrick Souverein and Olaf Klungel and Jeppesen, {Glenn Br{\o}de} and Flemming Nielsen and Kim Br{\o}sen and Hammer, {Helen S} and Oliver P{\"o}tz and Per Damkier and Erkka J{\"a}rvinen and Anton Potteg{\aa}rd and Stage, {Tore B}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.",

year = "2024",

month = dec,

doi = "10.1111/bcp.16190",

language = "English",

volume = "90",

pages = "3252--3262",

journal = "British Journal of Clinical Pharmacology",

issn = "0306-5251",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "12",

}

Iversen, DB, Dunvald, A-CD, Ernst, MT , Abtahi, S , Souverein, P , Klungel, O, Jeppesen, GB, Nielsen, F, Brøsen, K, Hammer, HS, Pötz, O, Damkier, P, Järvinen, E, Pottegård, A & Stage, TB 2024, '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', British Journal of Clinical Pharmacology, vol. 90, no. 12, pp. 3252-3262. https://doi.org/10.1111/bcp.16190

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. / Iversen, Ditte B; Dunvald, Ann-Cathrine Dalgård; Ernst, Martin Thomsen et al.
In: British Journal of Clinical Pharmacology, Vol. 90, No. 12, 12.2024, p. 3252-3262.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - 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

AU - Iversen, Ditte B

AU - Dunvald, Ann-Cathrine Dalgård

AU - Ernst, Martin Thomsen

AU - Abtahi, Shahab

AU - Souverein, Patrick

AU - Klungel, Olaf

AU - Jeppesen, Glenn Brøde

AU - Nielsen, Flemming

AU - Brøsen, Kim

AU - Hammer, Helen S

AU - Pötz, Oliver

AU - Damkier, Per

AU - Järvinen, Erkka

AU - Pottegård, Anton

AU - Stage, Tore B

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

KW - P-glycoprotein transporter

KW - antibiotics

KW - direct oral anticoagulants

KW - drug–drug interactions

KW - stroke

KW - systemic embolism

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U2 - 10.1111/bcp.16190

DO - 10.1111/bcp.16190

M3 - Article

C2 - 39160000

SN - 0306-5251

VL - 90

SP - 3252

EP - 3262

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

IS - 12

ER -

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

Bibliographical note

Funding

Keywords

UN SDGs

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