Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Pharmacol Rep. 2011;63(3):815-25. doi: 10.1016/s1734-1140(11)70594-1.
The aim of this study was to retrospectively evaluate the effect of polymorphisms in the CYP3A4, CYP3A5 and ABCB1 genes on the dose-adjusted concentration and dose requirement of cyclosporine A(CsA) in Chinese recipients during the early period after bone marrow or hematopoietic stem cell transplantation. Ninety-one bone marrow transplant recipients were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay or by direct sequencing for the C1236T, G2677T/A and C3435T polymorphisms in CYP3A418B, CYP3A53, and ABCB1, respectively. The concentration at zero before administration (C₀) and concentration at 2 h after administration (C₂) of whole blood CsA were measured by fluorescence polarization immunoassay. Dose-adjusted C₀ and C₂ were determined and compared among groups with different genotypes. Compared with CYP3A5*3/3 individuals, CYP3A51/1 subjects have a significantly lower dose-adjusted C₀ and C₂ at days 1-10 and a higher dose requirement for CsA at days 16-30 (p < 0.05). In addition, homozygotes for the ABCB1 3435T mutant have a significantly higher dose-adjusted C₀ and C₂ and a lower dose requirement compared with wildtype (p < 0.05). Similar results were also derived for carriers of the T-G-C haplotype in CYP3A5 producers compared with non-carriers (p < 0.05 and p < 0.01, respectively). In summary, the ABCB1 3435T SNP, T-G-C haplotype in CYP3A5 producers, and CYP3A53 SNP are all associated with differences in CsA pharmacokinetics and dose requirements during the first month after bone marrow or hematopoietic stem cell transplantation. Genetic testing can therefore help to determine initial dosage and individualize immunosuppressive therapy.
本研究旨在回顾性评估 CYP3A4、CYP3A5 和 ABCB1 基因多态性对骨髓或造血干细胞移植后早期中国受者环孢素 A（CsA）剂量调整浓度和剂量需求的影响。91 例骨髓移植受者通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析或直接测序，分别对 CYP3A418B、CYP3A53 和 ABCB1 的 C1236T、G2677T/A 和 C3435T 多态性进行基因分型。采用荧光偏振免疫法测定全血 CsA 给药前零时浓度（C0）和给药后 2 小时浓度（C2）。确定并比较不同基因型组的剂量调整 C0 和 C2。与 CYP3A5*3/3 个体相比，CYP3A51/1 患者在第 1-10 天的剂量调整 C0 和 C2 显著降低，在第 16-30 天的 CsA 剂量需求更高（p<0.05）。此外，ABCB1 3435T 突变纯合子与野生型相比，剂量调整 C0 和 C2 显著升高，剂量需求降低（p<0.05）。与非携带者相比，CYP3A5 产生者中 T-G-C 单倍型携带者也得出了类似的结果（分别为 p<0.05 和 p<0.01）。综上所述，ABCB1 3435T SNP、CYP3A5 产生者中的 T-G-C 单倍型和 CYP3A53 SNP 均与骨髓或造血干细胞移植后第一个月 CsA 药代动力学和剂量需求的差异相关。因此，基因检测有助于确定初始剂量并实现个体化免疫抑制治疗。
