Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro

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AIM: The aim of this study was to study potential cytochrome P450 induction by dicloxacillin.

METHODS: We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48h and changes in gene expression and enzyme activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 was investigated. Activation of nuclear receptors by dicloxacillin was assessed using luciferase assays.

RESULTS: Ten days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0-24h of omeprazole (CYP2C19) (geometric mean ratio (GMR) [95% confidence interval (CI)]: 0.33 [0.24-0.45]), tolbutamide (CYP2C9) (GMR [95% CI]: 0.73 [0.65-0.81]) and midazolam (CYP3A4) (GMR [95% CI]: 0.54 [0.41-0.72]). Additionally, other relevant pharmacokinetic parameters were affected indicating induction of CYP2C and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed statistically significant dose-dependent increase in P450 expression and activity by dicloxacillin, caused by activation of pregnane X receptor.

CONCLUSIONS: Dicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.

JournalBritish Journal of Clinical Pharmacology
Issue number3
Pages (from-to)510-519
Publication statusPublished - 2018

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  • Journal Article