Association of polymorphism of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR with the concentration of cyclosporin A in allogeneic haematopoietic stem cell transplantation recipients
Association of polymorphism of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR with the concentration of cyclosporin A in allogeneic haematopoietic stem cell transplantation recipients
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DOI：
10.1080/00498254.2021.1928791
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发表时间：
2021-05-21
期刊：
影响因子：
1.8
通讯作者：
Zhang, Zanling
中科院分区：
文献类型：
--
作者：
Wang, Linlin;Zeng, Guangting;Zhang, Zanling
环孢素a （CsA）的特点是治疗窗口窄，个体间药代动力学变异性高。在这项研究中，我们旨在确定CYP3A4、ABCB1、ABCC2、ABCG2、NFKB1、POR和PXR多态性与同种异体造血细胞移植（alloo - hsct）患者CsA浓度的关系。共40例接受CsA的同种异体造血干细胞受体进行了CYP3A4、ABCB1、ABCC2、ABCG2、NFKB1、POR和PXR多态性的基因分型。分析了多态性与CsA浓度的相关性。口服和静脉给药的CsA剂量调整谷浓度（Cssmin/D）差异有统计学意义（p < 0.001）。对于静脉给药CsA Cssmin/D， CYP3A4 rs2246709 （p = 0.015）、ABCC2 rs717620 （p = 0.024）、ABCG2 rs2231142 （p = 0.042）、PXR rs3732359 （p = 0.008）、PXR rs3814058 （p = 0.028）和PXR rs6785049 （p < 0.001）对CsA Cssmin/D有显著影响。对于口服给药CsA Cssmin/D， ABCC2 rs717620 （p = 0.009）和ABCG2 rs2231142 （p = 0.011）对CsA Cssmin/D有显著影响。这些结果表明，CYP3A4、ABCC2、ABCG2和PXR基因型与CsA Cssmin/D密切相关，这些snp适合用于确定CsA的适宜剂量。
Cyclosporin a (CsA) was characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability. In this study, we aimed to identify the association of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms with CsA concentrations in patients with allogeneic haematopoietic cell transplantation (allo-HSCT) based on the route of administration. A total of 40 allo-HSCT recipients receiving CsA were genotyped for CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms. The correlation between polymorphisms and CsA concentration was analysed. The CsA dose-adjusted trough concentration (Cssmin/D) of oral or intravenous administration was significantly different (p < 0.001). For CsA Cssmin/D of intravenous administration, CYP3A4 rs2246709 (p = 0.015), ABCC2 rs717620 (p = 0.024), ABCG2 rs2231142 (p = 0.042), PXR rs3732359 (p = 0.008), PXR rs3814058 (p = 0.028) and PXR rs6785049 (p < 0.001) had a significant effect on CsA Cssmin/D. For CsA Cssmin/D of oral administration, ABCC2 rs717620 (p = 0.009) and ABCG2 rs2231142 (p = 0.011) had a significant effect on CsA Cssmin/D. These results illustrated that the CYP3A4, ABCC2, ABCG2, and PXR genotypes were closely correlated with CsA Cssmin/D, suggesting these SNPs were suitable for determining the appropriate dose of CsA.