Abstract

1. 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.

2. 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.

3. 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.

4. 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.

摘要

1. 环孢菌素 a (CsA) 的特点是治疗窗口窄和个体间药代动力学变异性高。在本研究中，我们旨在根据给药途径确定异基因造血细胞移植 (allo-HSCT) 患者中CYP3A4、ABCB1、ABCC2、ABCG2、NFKB1、POR 和 PXR多态性与 CsA 浓度的关联。

2. 总共 40 名接受 CsA 的 allo-HSCT 受者进行了CYP3A4、ABCB1、ABCC2、ABCG2、NFKB1、POR 和 PXR多态性的基因分型。分析了多态性与CsA浓度之间的相关性。

3. 口服或静脉给药的 CsA 剂量调整谷浓度 (Cssmin/D) 显着不同 ( p  < 0.001)。对于环孢素Cssmin /静脉内给药的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 有显着影响。对于口服给药的 CsA Cssmin/D，ABCC2 rs717620 ( p  = 0.009) 和ABCG2 rs2231142 (p  = 0.011) 对 CsA Cssmin/D 有显着影响。

4. 这些结果表明CYP3A4、ABCC2、ABCG2和PXR基因型与 CsA Cssmin/D 密切相关，表明这些 SNP 适合确定适当的 CsA 剂量。