Short summary

Our study group has recently discovered a new and clinically important interaction between the antibiotic dicloxacillin and warfarin which was published in JAMA to significant interest. In a clinical study of healthy volunteers, we will study the clinical relevant risk of interaction between dicloxacillin and other drugs by assessing the influence of dicloxacillin on the enzymes in the liver that metabolizes drugs.

Rationale

Dicloxacillin is a broad-spectrum antibiotic prescribed for treatment of various infections with penicillinase producing methicillin bacteria in bones, skin and soft tissue, usually staphylococcus aureus infections. It is very commonly used, as dicloxacillin was prescribed to about 2% of the Danish population in 2014.

We recently demonstrated within a methodologically strong pharmacoepidemiological setting that dicloxacillin significantly reduces the effect of warfarin as measured by INR values. Within 2-4 weeks after starting treatment with dicloxacillin two thirds of patients treated with warfarin experienced therapeutic failure (an INR<2). The reason for this effect is unknown, but a similar effect for dicloxacillin has previously been described in a few reported cases. No well-established biological explanation is available.

Decreased plasma warfarin level was observed in one patient 7 days after treatment with dicloxacillin was initiated, which indicates an increased metabolism of warfarin. Thus induction of warfarin metabolism by dicloxacillin may explain our finding. Warfarin is administered orally as a 50:50 racemic mixture of the R- and S-enantiomer. The S-enantiomer is 2-5 times more potent than its R-enantiomer counterpart. The metabolism of warfarin is complex, but the S-enantiomer is primarily metabolized by the P450 drug metabolizing enzymes CYP2C9 and, to a minor extent, CYP3A4. Dicloxacillin has been shown to activate the pregnane X receptor (PXR) in vitro. PXR is a nuclear receptor, which is a known regulator of the expression of many drug-metabolizing enzymes, especially CYP3A4. In vitro, dicloxacillin exposure increased CYP3A4 mRNA and protein levels in liver cells, indicating that dicloxacillin induces CYP3A4 expression. This was not investigated for other CYP enzymes relevant for warfarin metabolism, especially CYP2C9.

We will perform a 2-phase randomized crossover study in healthy male volunteers using a low-dose cocktail of five different drugs that are markers of specific CYP enzyme activities. This cocktail consist of five different substrates midazolam (CYP3A4), dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19) and caffeine (CYP1A2).

Description of the cohort

12 young healthy male volunteers recruited at University of Southern Denmark.

Data and biological material

Data: concentrations of drugs and their metabolites; adverse reactions

Collaborating researchers and departments

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital

Professor Per Damkier, MD, PhD

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco and Clinical Pharmacology and Pharmaceutics, University of Southern Denmark

• Postdoc Tore Stage, MSc, PhD

• Professor Kim Brøsen, MD, DMSc