Key Laboratory of Drug Targeting and Drug Delivery System, West China School of Pharmacy, Sichuan University, No. 17, Section 3, South Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.
Eur J Clin Pharmacol. 2013 Nov;69(11):1917-25. doi: 10.1007/s00228-013-1552-2. Epub 2013 Jun 27.
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.
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.
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.
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.
CYP3A4 是细胞色素 P450 氧化酶的主要同工酶，参与约 60%药物的代谢，其表达水平在人体中差异很大。CYP3A4 受许多转录因子调节，其中已鉴定出孕烷 X 受体/甾体和异生素受体（PXR/SXR，NR1I2）为最关键的调节因子。PXR 中的遗传多态性（如 SNPs）可能影响 CYP3A4 的表达水平。尽管已经在 PXR 中发现了许多 SNPs，并表明它们影响 PXR 功能，但它们对人体 CYP3A4 表达的影响尚未得到很好的研究。因此，在中国健康受试者中进行了一项临床研究，以研究 PXR 多态性对瑞格列奈（CYP3A4 活性的内源性标志物）单独或与 PXR 诱导剂氟氯西林联合使用时的药代动力学的影响。
确定了 -298A>G 和 11193T>C 两个 SNP 作为标记 SNP，以代表 PXR 的总体遗传多态性谱。为了评估这两个 SNP 的潜在功能变化，招募了 24 名健康受试者进行瑞格列奈的药代动力学/药效学研究，同时使用或不使用氟氯西林。
AUC 和 T1/2 等药代动力学参数在 PXR 基因型组之间存在显著差异。发现-298G/G 和 11193C/C 两个 SNP 与较低的 PXR 活性相关，导致体内 CYP3A4 活性降低。给予氟氯西林后，观察到明显的药物相互作用。瑞格列奈的清除率在基因型依赖性方式下显著增加。具有-298G/G 和 11193C/C SNP 的受试者对氟氯西林的敏感性似乎较低。
我们的研究结果首次证明了 PXR 遗传多态性对瑞格列奈 PK 和 PD 的影响，并表明 PXR 基因型为-298G/G 和 11193C/C 的受试者的 3A4/2C8 消除率降低。此外，氟氯西林能够以基因型依赖性方式诱导 PXR 介导的 3A4/2C8 表达。
