Supporting safe use of antibiotics: Penicillinase-resistant penicillins as inducers of drug metabolism and drug transport

Research output: ThesisPh.D. thesis

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Abstract

Drug-drug interactions (DDIs) can increase the risk of adverse events and therapeutic failure and increase healthcare costs. Pharmacokinetic DDIs can be mediated through induction or inhibition of drug-metabolizing enzymes or drug transporters. In this thesis, we assessed the drug-metabolizing enzymes and drug transporters involved in the drug metabolism and drug transport of the most commonly prescribed oral drugs. Furthermore, we focused on two well-known antibiotics: flucloxacillin and dicloxacillin. We hypothesized that flucloxacillin induces cytochrome P450 (CYP) enzymes and that dicloxacill ininduces the drug transporter P-glycoprotein (P-gp). Furthermore, we hypothesized that the use of dicloxacillin could result in DDIs with a specific class of anticoagulants known as direct oral anticoagulants (DOACs).

In Paper 1, we aimed to map the drug-metabolizing enzymes and drug transporters responsible for the drug metabolism and drug transport of the 100 most prescribed oral drugs. We found that 89 of these 100 drugs undergo drug metabolism and/or are known to be transported by drug transporters. Furthermore, CYP3A4 is the most important drugmetabolizing enzyme, and P-gp is the most important drug transporter.

In Paper 2, we aimed to investigate if flucloxacillin induces CYP enzymes in healthy adults and human hepatocytes. We conducted a randomized, two-period, cross-over, clinical pharmacokinetic trial including 12 healthy adults who were taking flucloxacillin for 31 days. Using the Basel cocktail, we found that continuous treatment with flucloxacillin for 10 and 28 days, resulted in a weak induction of CYP3A4. This was also confirmed in vitro in human hepatocytes. In the same clinical trial, we also investigated whether flucloxacillin induces its own metabolism after 9 and 27 days of flucloxacillin treatment, thus being an autoinducer. We found that flucloxacillin is, indeed, an autoinducer; however, we were unable to determine if this has any clinical implications since the minimal inhibitory concentration (MIC) of the active metabolite is unknown. 

In Paper 3, we aimed to investigate if dicloxacillin is an inducer of the P-gp transporter in a clinical trial and in vitro in intestinal cells and human hepatocytes. This was investigated in a randomized, two-period, cross-over, clinical pharmacokinetic trial including 10 healthy adults. The healthy adults ingested dicloxacillin for 30 days. We found that dicloxacillin reduces the concentration of the P-gp probe drug dabigatran etexilate and the active metabolite dabigatran after 10 and 28 days of dicloxacillin treatment. In vitro, we found that dicloxacillin increases the expression of P-gp. Based on these findings, we believe that the reduction in the area under the curve (AUC) of dabigatran can be attributed to induction of intestinal P-gp by dicloxacillin. Furthermore, we conducted a register-based study in Paper 3. We aimed to investigate if co-treatment with dicloxacillin and DOACs enhances the risk of stroke/systemic embolism. We used a Danish cohort of dicloxacillin users co-treated with a DOAC (dabigatran etexilate, apixaban, edoxaban, or rivaroxaban). Our findings did not show an increased risk of stroke/systemic embolism when DOACs were used concomitantly with dicloxacillin. 

We conclude that the majority of drugs undergo drug metabolism and/or are known to be transported by drug transporters. Among these drugs, CYP3A4 and P-gp play a crucial role in these processes. Flucloxacillin is a weak inducer of CYP3A4, and caution should be exercised when administering CYP3A4 substrates with a narrow therapeutic range simultaneously with flucloxacillin. Flucloxacillin can also be categorized as an autoinducer, but its clinical impact is unknown. Furthermore, dicloxacillin is an inducer of intestinal P-gp, and caution should be exercised when administering substrates of intestinal P-gp with a narrow therapeutic range simultaneously with dicloxacillin. However, coadministration of DOACs and dicloxacillin did not increase the risk of stroke/systemic embolism, even though DOACs are metabolized by CYP3A4 and/or transported by P-gp. 
Translated title of the contributionStøtte til sikker brug af antibiotika: Penicillinase-resistente penicilliner som inducere af lægemiddelmetabolisme og lægemiddeltransport
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Stage, Tore B., Principal supervisor
  • Pottegård, Anton, Co-supervisor
  • Brøsen, Kim, Co-supervisor
  • Damkier, Per, Co-supervisor
Date of defence13. Oct 2023
Publisher
DOIs
Publication statusPublished - 21. Sept 2023

Keywords

  • Drug-drug interaction
  • CYP enzymes
  • Drug transporters
  • Metabolism
  • Induction

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