Trial reportEuropean journal of clinical pharmacology2013
PXR polymorphisms and their impact on pharmacokinetics/pharmacodynamics of repaglinide in healthy Chinese volunteers.
Trial report in European journal of clinical pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 22 citations in OpenAlex.
- Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users.British journal of clinical pharmacology · 2024Trial
- Pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of single and continuous intravenous infusion of SPT-07A in healthy volunteers.European journal of clinical pharmacology · 2020Trial
- CYP2C8-Mediated Drug-Drug Interactions and the Factors Influencing the Interaction Magnitude.Drug design, development and therapy · 2025Review
- Interaction between posaconazole and flucloxacillin in a lung transplant patient: decrease in plasma exposure of posaconazole and possible undertreatment of invasive aspergillosis: case report.BMC pulmonary medicine · 2022Article
- Why We Need to Take a Closer Look at Genetic Contributions to CYP3A Activity.Frontiers in pharmacology · 2022Review
- Concomitant Treatment with Voriconazole and Flucloxacillin: A Combination to Avoid.Antibiotics (Basel, Switzerland) · 2021Article
- Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation.Infection and drug resistance · 2018Review
- Impact of chronic unpredicted mild stress-induced depression on repaglinide fate via glucocorticoid signaling pathway.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeCYP3A4 is the main isoform of cytochrome P450 oxidases involved in the metabolism of approximately 60 % drugs, and its expression level is highly variable in human subjects. CYP3A4 is regulated by many transcription factors, among which the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR, NR1I2) have been identified as the most critical. Genetic polymorphisms (such as SNPs) in PXR may affect the expression level of CYP3A4. Although numerous SNPs have been identified in PXR and have appeared to affect PXR function, their impact on the expression of CYP3A4 in human subjects has not been well studied. Thus, a clinical study in healthy Chinese subjects was conducted to investigate the impact of PXR polymorphisms on repaglinide (an endogenous marker for CYP3A4 activity) pharmacokinetics used alone or in combination with a PXR inducer, flucloxacillin.
methodTwo SNPs, -298A>G and 11193T>C, were identified as the tag SNPs to represent the overall genetic polymorphic profile of PXR. To evaluate the potential functional change of these two SNPs, 24 healthy subjects were recruited in a pharmacokinetics/pharmacodynamics study of repaglinide with or without flucloxacillin.
resultsThe pharmacokinetic parameters including AUC and T1/2 were significantly different among the PXR genotype groups. The SNPs of -298G/G and 11193C/C were found to be associated with a lower PXR activity resulting in reduction of CYP3A4 activity in vivo. After administration of flucloxacillin, a significant drug-drug interaction was observed. The clearance of repagnilide was significantly increased by concomitant flucloxacillin in a genotype dependent manner. The subjects with SNPs of -298G/G and 11193C/C appeared to be less sensitive to flucloxacillin.
conclusionOur study results demonstrated for the first time the impact of genetic polymorphisms of PXR on the PK and PD of repaglinide, and showed that subjects with genotype of -298G/G and 11193C/C in PXR has a decreased elimination rate of 3A4/2C8. Furthermore, flucloxacillin was able to induce 3A4/2C8 expression mediated by PXR in a genotype dependent manner.
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