PXR polymorphisms and their impact on pharmacokinetics/pharmacodynamics of repaglinide in healthy Chinese volunteers

Eur J Clin Pharmacol. 2013 Nov;69(11):1917-25. doi: 10.1007/s00228-013-1552-2. Epub 2013 Jun 27.


Purpose: CYP3A4 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.

Method: Two 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.

Results: The 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.

Conclusion: Our 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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Anti-Bacterial Agents / blood
  • Anti-Bacterial Agents / pharmacology*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Asian People / genetics
  • Blood Glucose / analysis
  • Carbamates / blood
  • Carbamates / pharmacology*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A / genetics
  • Drug Interactions
  • Floxacillin / blood
  • Floxacillin / pharmacology*
  • Genotype
  • Healthy Volunteers
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacology*
  • Piperidines / blood
  • Piperidines / pharmacology*
  • Polymorphism, Single Nucleotide
  • Pregnane X Receptor
  • Receptors, Steroid / genetics*
  • Receptors, Steroid / metabolism


  • Anti-Bacterial Agents
  • Blood Glucose
  • Carbamates
  • Hypoglycemic Agents
  • NR1I2 protein, human
  • Piperidines
  • Pregnane X Receptor
  • Receptors, Steroid
  • Floxacillin
  • repaglinide
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human