CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation
CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation
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DOI：
10.1016/j.clpt.2004.01.009
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发表时间：
2004-05-01
影响因子：
6.7
通讯作者：
Marquet, P
中科院分区：
文献类型：
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作者：
Anglicheau, D;Thervet, E;Marquet, P
背景：免疫抑制药物环孢素（INN，环孢素）是细胞色素P450（CYP）3A和多药耐药1（MDR1）基因产物P-糖蛋白的底物，其药代动力学特征在个体之间存在很大差异。这些基因中的一些单核苷酸多态性 (SNP) 与蛋白质表达缺陷和体内活性降低有关。我们推测，在肾移植受者中，这些 SNP 可能与环孢素药代动力学的个体差异相关。 目的：在 106 名肾移植患者中，我们回顾性评估了 4 个 MDR1 SNP [T-129C、C1236T、G2677(T,A) 和 C3435T] 和 CYP3A5*1/*3 SNP 对环孢素药代动力学的影响。环孢素药代动力学参数和暴露指数。结果：8.5% 的患者存在 CYP3A5*1 等位基因。 MDR1 C1236T、G2677(T,A) 和 C3435T SNP 很常见（对于变异纯合基因型分别为 17.9%、18.9% 和 33%），并且表现出不完全连锁不平衡。环孢素药代动力学参数均与 CYP3A5 遗传多态性无关。与突变等位基因携带者相比，MDR1 C1236T SNP 野生型基因型患者的剂量调整峰值药物浓度 (-16%) (P < .02) 和剂量调整浓度-时间曲线下面积 (AUC) 值 (-14%) (P < .05) 略有降低，但前 4 小时显着降低。包括 MDR1 C1236T、G2677(T,A) 和 C3435T SNP 在内的单倍型分析显示，单倍型与环孢菌素药代动力学或全身暴露之间没有显着相关性，尽管 T-T-T 单倍型在前 4 小时内剂量调整后的 AUC 值和 12 小时给药间隔内的 AUC 值没有显着趋势。结论：存在CYP3A5 SNP 不能解释稳定肾移植患者中环孢素药代动力学的高度变异性。尽管发现 MDR1 CI236T SNP 的关联性较弱，但 MDR1 SNP 不太可能对临床实践中的环孢素剂量优化有用。
Background: The immunosuppressive drug cyclosporine (INN, ciclosporin), whose pharmacokinetic characteristics vary greatly among individuals, is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNPs) in these genes are associated with deficient protein expression and reduced in vivo activity. We postulated that, in renal transplant recipients, these SNPs could be associated with interindividual variations in cyclosporine pharmacokinetics.Purpose: In 106 renal transplant patients, we evaluated retrospectively the effects of 4 MDR1 SNPs [T-129C, C1236T, G2677(T,A), and C3435T] and of the CYP3A5*1/*3 SNP on cyclosporine pharmacokinetic parameters and exposure indices.Results: The CYP3A5*1 allele was present in 8.5% of patients. The MDR1 C1236T, G2677(T,A), and C3435T SNPs were frequent (17.9%, 18.9%, and 33%, respectively, for the variant homozygous genotype) and exhibited incomplete linkage disequilibrium. None of the cyclosporine pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism. Patients with the wild-type genotype in MDR1 C1236T SNP had slightly but significantly lower dose-adjusted peak drug concentrations (-16%) (P < .02) and dose-adjusted area under the concentration-time curve (AUC) values over the first 4 hours (-14%) (P < .05) as compared with mutated allele carriers. Haplotype analysis including MDR1 C1236T, G2677(T,A), and C3435T SNPs showed no significant association between haplotypes and cyclosporine pharmacokinetics or systemic exposure, although there was a nonsignificant trend toward higher dose-adjusted AUC values over the first 4 hours and AUC over the 12-hour administration interval for the T-T-T haplotype.Conclusion: The presence of the CYP3A5 SNP does not explain the high variability of cyclosporine pharmacokinetics in stable renal transplant patients. Despite the weak association found for the MDR1 CI236T SNP, MDR1 SNPs are unlikely to be useful for cyclosporine dose optimization in clinical practice.