Details

Autor(en) / Beteiligte

• Stage, Tore Bjerregaard
• Graff, Magnus
• Wong, Susan
• Rasmussen, Louise Ladebo
• Nielsen, Flemming
• Pottegård, Anton
• Brøsen, Kim
• Kroetz, Deanna L.
• Khojasteh, S. Cyrus
• Damkier, Per

Titel

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

Ist Teil von

• British journal of clinical pharmacology, 2018-03, Vol.84 (3), p.510-519

Ort / Verlag

England: John Wiley and Sons Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Aim The aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin. Methods We performed an open‐label, randomized, two‐phase, five‐drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1 g dicloxacillin three times daily for 10 days. Plasma and urine were collected over 24 h and the concentration of all five drugs and their primary metabolites was determined using a liquid chromatography coupled to triple quadrupole mass spectrometry method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48 h and changes in gene expression and the activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 were investigated. The activation of nuclear receptors by dicloxacillin was assessed using luciferase assays. Results A total of 10 days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration–time curve from 0 to 24 h for 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 the induction of CYP2C‐ and CYP3A4‐mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed a statistically significant dose‐dependent increase in CYP expression and activity by dicloxacillin, caused by activation of the 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.