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

Br J Clin Pharmacol. 2018 Mar;84(3):510-519. doi: 10.1111/bcp.13467. Epub 2018 Jan 10.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Bacterial Agents / pharmacology
  • Area Under Curve
  • Chromatography, Liquid
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C19 / biosynthesis
  • Cytochrome P-450 CYP2C19 / drug effects*
  • Cytochrome P-450 CYP2C9 / biosynthesis
  • Cytochrome P-450 CYP2C9 / drug effects*
  • Cytochrome P-450 CYP3A / biosynthesis
  • Cytochrome P-450 CYP3A / drug effects*
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / drug effects
  • Dicloxacillin / pharmacology*
  • Drug Interactions
  • Enzyme Induction / drug effects
  • Female
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Humans
  • Male
  • Mass Spectrometry
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Cytochrome P-450 Enzyme System
  • Dicloxacillin
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human