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

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Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro. / Stage, Tore Bjerregaard; Graff, Magnus; Wong, Susan; Rasmussen, Louise Ladebo; Nielsen, Flemming; Pottegård, Anton; Brøsen, Kim; Kroetz, Deanna L; Cyrus Khojasteh, S; Damkier, Per.

In: British Journal of Clinical Pharmacology (Online), 04.11.2017.

Research output: Research - peer-reviewJournal article

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@article{d53c53f28c8b4ebcb82a410f5daf3535,
title = "Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro",
abstract = "AIM: The aim of this study was to study potential cytochrome P450 induction by dicloxacillin.METHODS: We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48h and changes in gene expression and enzyme activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 was investigated. Activation of nuclear receptors by dicloxacillin was assessed using luciferase assays.RESULTS: Ten days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0-24h of 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 induction of CYP2C and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed statistically significant dose-dependent increase in P450 expression and activity by dicloxacillin, caused by activation of 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.",
keywords = "Journal Article",
author = "Stage, {Tore Bjerregaard} and Magnus Graff and Susan Wong and Rasmussen, {Louise Ladebo} and Flemming Nielsen and Anton Pottegård and Kim Brøsen and Kroetz, {Deanna L} and {Cyrus Khojasteh}, S and Per Damkier",
note = "This article is protected by copyright. All rights reserved.",
year = "2017",
month = "11",
doi = "10.1111/bcp.13467",
journal = "British Journal of Clinical Pharmacology (Online)",
issn = "1365-2125",
publisher = "Wiley-Blackwell",

}

RIS

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 - 2017/11/4

Y1 - 2017/11/4

N2 - AIM: The aim of this study was to study potential cytochrome P450 induction by dicloxacillin.METHODS: We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48h and changes in gene expression and enzyme activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 was investigated. Activation of nuclear receptors by dicloxacillin was assessed using luciferase assays.RESULTS: Ten days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0-24h of 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 induction of CYP2C and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed statistically significant dose-dependent increase in P450 expression and activity by dicloxacillin, caused by activation of 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 induction by dicloxacillin.METHODS: We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48h and changes in gene expression and enzyme activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 was investigated. Activation of nuclear receptors by dicloxacillin was assessed using luciferase assays.RESULTS: Ten days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0-24h of 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 induction of CYP2C and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed statistically significant dose-dependent increase in P450 expression and activity by dicloxacillin, caused by activation of 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

JO - British Journal of Clinical Pharmacology (Online)

T2 - British Journal of Clinical Pharmacology (Online)

JF - British Journal of Clinical Pharmacology (Online)

SN - 1365-2125

ER -