Dataset Information

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

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.

SUBMITTER: Stage TB

PROVIDER: S-EPMC5809358 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Stage Tore Bjerregaard TB Graff Magnus M Wong Susan S Rasmussen Louise Ladebo LL Nielsen Flemming F Pottegård Anton A Brøsen Kim K Kroetz Deanna L DL Khojasteh S Cyrus SC Damkier Per P

British journal of clinical pharmacology 20180110 3

<h4>Aim</h4>The aim of this study was to study potential cytochrome P450 (CYP) induction by dicloxacillin.<h4>Methods</h4>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 ...[more]

PMID: 29105855

Similar Datasets

Project description:Background Genetic diversity of cytochrome P450 2C subfamily metabolizing epoxyeicosatrienoic acids, vasoactive substances with a wide range of biological actions in the cardiovascular system, contributes to the molecular basis of coronary artery disease (CAD). Association between genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and CAD risk has been extensively investigated in Chinese, Japanese, Korean and other Asian populations whereas a few studies have been done in Europeans. The present study investigated whether common single nucleotide polymorphisms (SNPs) of CYP2C8, CYP2C9 and CYP2C19 genes are important risk factors of CAD in a Russian population. Methods DNA samples from 1,255 unrelated subjects comprising 561 patients with angiographically diagnosed CAD and 694 age- and sex-matched healthy subjects were genotyped for six SNPs such as rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. Results SNP rs4918758 of CYP2C9 was associated with decreased risk of CAD with odds ratio 0.61 adjusted for sex and age (codominant genetic model, 95% CI: 0.41–0.92, P=0.038, Q =0.20). Log-likelihood ratio test pointed out epistatic interactions between SNPs rs9332242 and rs61886769 of CYP2C9 at a codominant genetic model (Pinteraction =0.02). Moreover, SNP rs9332242 of CYP2C9 showed a trend towards association with increased CAD risk in cigarette smokers (P=0.049, Q =0.29). Bioinformatic analysis using the SNP prediction tool revealed a regulatory potential for all SNPs associated with CAD. Conclusions To our knowledge, the present study is the first to show that polymorphisms rs4918758 and rs9332242 of CYP2C9 represent significant genetic markers of CAD susceptibility in Europeans. A validation of genetic markers associated with CAD risk in different races and ethnicities may cut corners between discovery and clinical qualification of such markers for the purposes of translational medicine. The study was supported by the Russian Science Foundation.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets