Pediatric Nephrology Unit, Ospedale Maggiore IRCCS, Via F. Sforza 35, 20133 Milan, Italy.
Pharmacol Rep. 2010 Nov-Dec;62(6):1159-69. doi: 10.1016/s1734-1140(10)70378-9.
The main genes involved in the pharmacokinetics of immunosuppressive drugs are those encoding cytochrome P450 (CYP) family enzymes and multidrug resistance 1 (ABCB1). In this study, 87 Italian teenagers with transplanted kidneys (mean age 11.6 ± 4.8 years) receiving calcineurin inhibitors (CNIs) were genotyped for the single nucleotide polymorphisms (SNPs) CYP3A51/3 and CYP3A41B for CYP3A, and C1236T, G2677T/A, C3435T and IVS21+49 for ABCB1, and retrospectively evaluated for the influence of the screened SNPs on CNI blood level at different post-transplantation times. The CYP3A51 allele was present in 7% of the patients, and the CYP3A41B allele was present in 3% of patients. The ABCB1 C1236T, G2677T/A and C3435T SNPs C, G and T occurred frequently (55%, 53% and 54%, respectively). The frequency of the T allele of IVS21+49 was 86%. The frequency of SNPs in both genes was comparable with that reported in other European Caucasian populations but different from that found in Asians or Afro-Americans. None of the cyclosporine (CsA) pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism, whereas the presence of the A allele in some patients was responsible for the required administration of a significantly increased dose of tacrolimus (Tac) that was necessary to reach therapeutic target levels. None of the Tac pharmacokinetic parameters were associated with ABCB1 SNPs, but ABCB1 SNPs had early effects on the CsA exposure index and dose requirements. In conclusion, because SNPs of the CYP3A and ABCB1 genes may be associated with CNI pharmacokinetic parameters and exposure indices, pre-transplant genetic screening should be considered in order to avoid immunosuppressant-related adverse events.
参与免疫抑制剂药代动力学的主要基因是编码细胞色素 P450（CYP）家族酶和多药耐药蛋白 1（ABCB1）的基因。在这项研究中，对 87 名接受钙调神经磷酸酶抑制剂（CNI）治疗的意大利移植肾青少年（平均年龄 11.6±4.8 岁）进行了 CYP3A 单核苷酸多态性（SNP）CYP3A51/3 和 CYP3A41B 以及 ABCB1 的 C1236T、G2677T/A、C3435T 和 IVS21+49 的基因分型，并回顾性评估了这些 SNP 对不同移植后时间 CNI 血药浓度的影响。患者中存在 CYP3A51 等位基因的比例为 7%，存在 CYP3A41B 等位基因的比例为 3%。ABCB1 的 C1236T、G2677T/A 和 C3435T SNP 的 C、G 和 T 发生频率较高（分别为 55%、53%和 54%）。IVS21+49 的 T 等位基因频率为 86%。两个基因的 SNP 发生频率与其他欧洲白种人群报告的频率相似，但与亚洲或非裔美国人的频率不同。环孢素（CsA）药代动力学参数均与 CYP3A5 遗传多态性无关，而某些患者 A 等位基因的存在导致需要显著增加他克莫司（Tac）的剂量以达到治疗靶标水平。Tac 的药代动力学参数均与 ABCB1 SNP 无关，但 ABCB1 SNP 对 CsA 暴露指数和剂量需求有早期影响。总之，由于 CYP3A 和 ABCB1 基因的 SNP 可能与 CNI 药代动力学参数和暴露指数相关，因此应考虑在移植前进行基因筛查，以避免与免疫抑制剂相关的不良事件。
