Department of Surgical and Medical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Av. Elvas s/n 06071, Badajoz, Spain.
Eur J Clin Pharmacol. 2013 Mar;69(3):385-93. doi: 10.1007/s00228-012-1355-x. Epub 2012 Aug 11.
There is a great deal of controversy regarding the clinical impact of genetic variants in patients receiving cyclosporine (CsA) as immunosuppressant therapy. We have investigated the effect of polymorphisms in the CYP3A and ABCB1 genes on CsA pharmacokinetics, acute rejection incidence and drug-related side effects in renal transplant recipients
The presence of CYP3A53, CYP3A41B and ABCB1 C1236T, G2677T/A and C3435T polymorphisms was assessed in 68 patients and retrospectively associated with pharmacokinetic and clinical parameters at 1 week and 1, 5 and 12 months after transplantation.
Only minor associations were found between the tested polymorphisms and CsA pharmacokinetics. Most notably, CYP3A5 expressers showed lower blood trough levels than non-expressers in the first week after grafting (32.5 ± 14.7 vs. 55.1 ± 3.8 ng/ml per mg/day per kilogram). In terms of CsA-induced adverse effects, the incidence of nephrotoxicity was higher in carriers of the ABCB1 3435TT genotype and in those patients carrying four to six variants in the three ABCB1 loci [odds ratio (OR) 4.2, 95 % confidence interval (CI) 1.3-13.9, p = 0.02 and OR 3.6, 95 % CI 1.1-11.8, p = 0.05, respectively]. These subjects with four to six ABCB1 variants were also at higher risk for gingival hyperplasia (OR 3.29, 95 % CI 1.1-10.3, p = 0.04). Renal function and the incidence of neurotoxicity and of acute rejection did not vary across the different genotypes.
ABCB1 polymorphisms may be helpful in predicting certain CsA-related side effects in renal transplant recipients. Our results also suggest that the mechanisms underlying these genetic associations are most likely independent of the drug's trough blood concentrations.
在接受环孢素（CsA）作为免疫抑制剂治疗的患者中，基因变异对临床的影响存在很大争议。我们研究了 CYP3A 和 ABCB1 基因多态性对肾移植受者 CsA 药代动力学、急性排斥反应发生率和药物相关副作用的影响。
在 68 例患者中检测了 CYP3A53、CYP3A41B 和 ABCB1 C1236T、G2677T/A 和 C3435T 多态性，并回顾性分析了移植后 1 周、1、5 和 12 个月时与药代动力学和临床参数的相关性。
在所测试的多态性与 CsA 药代动力学之间仅发现了一些微小的关联。最值得注意的是，在移植后第一周，CYP3A5 表达者的血药谷浓度低于非表达者（32.5 ± 14.7 与 55.1 ± 3.8 ng/ml/天/毫克/千克）。就 CsA 引起的不良反应而言，ABCB1 3435TT 基因型携带者和携带三个 ABCB1 基因座中 4 到 6 种变异的患者发生肾毒性的发生率更高[比值比（OR）4.2，95%置信区间（CI）1.3-13.9，p = 0.02 和 OR 3.6，95%CI 1.1-11.8，p = 0.05]。这些携带 4 到 6 种 ABCB1 变异的患者也有更高的牙龈增生风险（OR 3.29，95%CI 1.1-10.3，p = 0.04）。肾功能以及神经毒性和急性排斥反应的发生率在不同基因型之间没有差异。
ABCB1 多态性可能有助于预测肾移植受者中某些与 CsA 相关的副作用。我们的结果还表明，这些遗传关联的机制很可能独立于药物的血药谷浓度。
