Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients
Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients
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DOI：
10.1097/01.asn.0000073901.94759.36
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发表时间：
2003-07-01
影响因子：
13.6
通讯作者：
Thervet, E
中科院分区：
文献类型：
--
作者：
Anglicheau, D;Verstuyft, CL;Thervet, E
免疫抑制药物他克莫司的药代动力学特征显示出很大的个体间差异，是多药耐药1（MDR 1）基因产物P-糖蛋白（P-gp）的底物。MDR 1的一些单核苷酸多态性（SNP）与P-gp的体内活性相关。因为已知P-gp控制他克莫司的肠道吸收，所以推测这些多态性与肾移植受者中他克莫司的药代动力学变化相关。本研究的目的是在81例肾移植受者的回顾性研究中评估可能与P-gp功能相关的4种常见MDR 1 SNP（外显子1b中的T-129 C，外显子12中的1236 C>T，外显子21中的2677 G>T，A和外显子26中的3435 C>T）对他克莫司剂量和浓度/剂量比的影响。与普通人群一样，外显子12、21和26的SNP频率较高（变异纯合基因型分别为16、17.3和22.2%），并表现出不完全连锁不平衡。在他克莫司治疗后1个月，外显子21 SNP与他克莫司日剂量（P ≤ 0.05）和浓度/剂量比（P ≤ 0.02）显著相关。对于该SNP，纯合子患者的他克莫司剂量需求比野生型患者高40%。野生型患者的浓度/剂量比低36%，表明对于给定剂量，他们的他克莫司血药浓度较低。单倍型分析证实了这些结果，并建议外显子26和21 SNP可能与他克莫司剂量需求。MDR 1基因的基因型监测可可靠地预测肾移植受者他克莫司的最佳剂量，并可预测个体患者获得足够免疫抑制所需的初始日剂量。
The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 2 1, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P less than or equal to 0.05) and the concentration/dose ratio (P less than or equal to 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.