Premium
Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro
Author(s) -
Stage Tore Bjerregaard,
Graff Magnus,
Wong Susan,
Rasmussen Louise Ladebo,
Nielsen Flemming,
Pottegård Anton,
Brøsen Kim,
Kroetz Deanna L.,
Khojasteh S. Cyrus,
Damkier Per
Publication year - 2018
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13467
Subject(s) - dicloxacillin , cyp3a4 , chemistry , cyp2b6 , cyp2c19 , pharmacokinetics , pharmacology , in vivo , cyp3a , cyp1a2 , cytochrome p450 , metabolism , medicine , antibiotics , biochemistry , ampicillin , microbiology and biotechnology , biology
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.