Back to Search
Start Over
Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro
- Source :
- British journal of clinical pharmacology. 84(3)
- Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- Adult
Male
Cross-Over Studies
Mass Spectrometry
Anti-Bacterial Agents
Cytochrome P-450 CYP2C19
Young Adult
Cytochrome P-450 Enzyme System
Drug Metabolism
Area Under Curve
Enzyme Induction
Hepatocytes
Cytochrome P-450 CYP3A
Humans
Dicloxacillin
Drug Interactions
Female
Chromatography, Liquid
Cytochrome P-450 CYP2C9
Subjects
Details
- ISSN :
- 13652125
- Volume :
- 84
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- British journal of clinical pharmacology
- Accession number :
- edsair.pmid..........16df316fc4abfc0926e32c3e34b7d8bb