TY - JOUR
T1 - Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro
AU - Stage, Tore Bjerregaard
AU - Graff, Magnus
AU - Wong, Susan
AU - Rasmussen, Louise Ladebo
AU - Nielsen, Flemming
AU - Pottegård, Anton
AU - Brøsen, Kim
AU - Kroetz, Deanna L
AU - Cyrus Khojasteh, S
AU - Damkier, Per
N1 - This article is protected by copyright. All rights reserved.
PY - 2018/3
Y1 - 2018/3
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1111/bcp.13467
DO - 10.1111/bcp.13467
M3 - Journal article
C2 - 29105855
SN - 0306-5251
VL - 84
SP - 510
EP - 519
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 3
ER -