Worldwide there is an increase in antibiotic resistance which may have potential fatal long-term consequences. This is due to extensive use and sometimes misuse of antibiotics in the treatment of harmless infections. The aim of this study is to investigate if treatment with flucloxacillin increases drug metabolism in healthy volunteers through induction of cytochrome P450 (CYP) enzymes, CYP1A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The hypothesis is based on an in vitro study showing that flucloxacillin activates a receptor (PXR) responsible for transcription of CYP enzymes. Trial subjects will ingest flucloxacillin for 31 days and at day 10 and 28 ingest a cocktail of 6 drugs to determine if the CYP enzymes have been induced. Plasma and urine will be drawn over 72 hours to determine the concentration of the 6 drugs and their metabolites. Change in flucloxacillin concentration will also be measured at day 9 and 27 to establish if flucloxacillin induces its own metabolism.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
14
Healthy volunteers will take 2x500 mg flucloxacillin 3 times a day for 31 days. The investigators will measure the baseline concentration of the 6-cocktaildrugs and flucloxacillin before start of 31 days of flucloxacillin treatment. On day 9 and 27 the investigators will measure the concentration of flucloxacillin. On day 10 and 28 the investigators will measure the concentration of the 6 cocktaildrugs
University of Southern Denmark
Odense, Region Syddanmark, Denmark
Change in Area under curve (AUC) of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Baseline and day 28
Change in AUC of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in AUC of the metabolite of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in Peak Plasma concentration (Cmax) of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in Cmax of the metabolite of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in Time to reach Cmax (Tmax) of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in Tmax of the metabolite of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in Renal Clearence (CLr) of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in CLr of the metabolite of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in Elimination half-life (T1/2) of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in T1/2 of the metabolite of midazolam
Change in the activity of the drug metabolizing enzyme CYP3A4
Time frame: Day 10 and 28
Change in AUC of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in AUC of the metabolite of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in Cmax of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in Cmax of the metabolite of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in Tmax of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in Tmax of the metabolite of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in CLr of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in CLr of the metabolite of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in T1/2 of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in T1/2 of the metabolite of metoprolol
Change in the activity of the drug metabolizing enzyme CYP2D6
Time frame: Day 10 and 28
Change in AUC of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in AUC of the metabolite of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in Cmax of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in Cmax of the metabolite of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in Tmax of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in Tmax of the metabolite of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in CLr of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in CLr of the metabolite of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in T1/2 of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in T1/2 of the metabolite of omeprazole
Change in the activity of the drug metabolizing enzyme CYP2C19
Time frame: Day 10 and 28
Change in AUC of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in AUC of the metabolite of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in Cmax of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in Cmax of the metabolite of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in Tmax of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in Tmax of the metabolite of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in CLr of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in CLr of the metabolite of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in T1/2 of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in T1/2 of the metabolite of losartan
Change in the activity of the drug metabolizing enzyme CYP2C9
Time frame: Day 10 and 28
Change in AUC of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in AUC of the metabolite of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in Cmax of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in Cmax of the metabolite of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in Tmax of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in Tmax of the metabolite of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in CLr of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in CLr of the metabolite of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in T1/2 of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in T1/2 of the metabolite of efavirenz
Change in the activity of the drug metabolizing enzyme CYP2B6
Time frame: Day 10 and 28
Change in AUC of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in AUC of the metabolite of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in Cmax of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in Cmax of the metabolite of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in Tmax of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in Tmax of the metabolite of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in CLr of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in CLr of the metabolite of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in T1/2 of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in T1/2 of the metabolite of caffeine
Change in the activity of the drug metabolizing enzyme CYP1A2
Time frame: Day 10 and 28
Change in AUC of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in AUC of the metabolite of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in Cmax of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in Cmax of the metabolite of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in Tmax of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in Tmax of the metabolite of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in CLr of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in CLr of the metabolite of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in T1/2 of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
Change in T1/2 of the metabolite of flucloxacillin
Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Time frame: Day 9 and 27
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