多药耐药基因1（MDR1）多态性对土耳其肾移植患者他克莫司血药浓度的影响。
Effect of MDR1 polymorphisms on the blood concentrations of tacrolimus in Turkish renal transplant patients.
作者信息
Ciftci H S, Ayna T K, Caliskan Y K, Guney I, Bakkaloglu H, Nane I, Aydin A E, Turkmen A, Gurtekin M
机构信息
Medical Biology Department, Istanbul Medicine Faculty, Istanbul University, Capa, Istanbul, Turkey.
出版信息
Transplant Proc. 2013 Apr;45(3):895-900. doi: 10.1016/j.transproceed.2013.02.055.
BACKGROUND
Tacrolimus, a calcineurin inhibitör, is prescribed to prevent allograft rejection in renal transplantation. Tacrolimus not only has a narrow therapeutic index, but also shows significant interindividual differences. The absorption and metabolism of this drug are affected by multidrug resistance (MDR) 1 gene polymorphisms that correlated with single-nucleotide polymorphisms (SNPs) affecting in vivo P-glycoprotein activity. This study investigated associations of MDR1 gene C3435T polymorphism with tacrolimus blood concentrations and dose requirements as well as acute rejection episodes among Turkish renal transplant patients.
METHODS
One hundred living-donor transplant recipients and 150 healthy control subjects underwent C3435T genotyping using polymerase chain reaction-restriction fragment length polymorphism. Blood concentrations of tacrolimus were determined with the cloned enzyme donor immunoassay.
RESULTS
The CC, CT, and TT genotype frequencies among patients were, respectively, 44.0%, 33.0%, and 23.0% versus 36.7%, 43.3%, and 20.0% among control subjects. There was no significant difference between (P = .061; P = .102; P = .211; respectively). The ratio of blood concentration to dose of tacrolimus for patients with mutant homozygous 3435 TT genotype was higher than that of wild-type 3435 CC genotype homozygous individuals. The doses for these patients were lower at 1, 3, and 12 months (P = .048; P = .03; P = .041, respectively). There were no significant differences between the groups regarding coprescription of drugs that affect tacrolimus concentrations, such as diltiazem. Acute rejection episodes were not associated with the CC vs CT or TT genotypes: odds ratio (OR), 0.517 (95% confidence interval [CI], 0.190-1.407; P = .192); OR 1.558 (95% CI, 0.587-4.136; P = .372); OR 1.346; (95% CI, 0.456-3.968; P = .590), respectively.
CONCLUSIONS
Determination of MDR1 polymorphism may help to achieve target of tacrolimus blood concentrations.
背景
他克莫司是一种钙调神经磷酸酶抑制剂，用于预防肾移植中的同种异体移植排斥反应。他克莫司不仅治疗指数狭窄，而且个体间差异显著。该药物的吸收和代谢受多药耐药（MDR）1基因多态性影响，这些多态性与影响体内P-糖蛋白活性的单核苷酸多态性（SNP）相关。本研究调查了土耳其肾移植患者中MDR1基因C3435T多态性与他克莫司血药浓度、剂量需求以及急性排斥反应发作之间的关联。
方法
100名活体供体移植受者和150名健康对照者采用聚合酶链反应-限制性片段长度多态性方法进行C3435T基因分型。采用克隆酶供体免疫分析法测定他克莫司的血药浓度。
结果
患者中CC、CT和TT基因型频率分别为44.0%、33.0%和23.0%，而对照者中分别为36.7%、43.3%和20.0%。两者之间无显著差异（P分别为0.061、0.102、0.211）。突变纯合3435 TT基因型患者的他克莫司血药浓度与剂量之比高于野生型3435 CC基因型纯合个体。这些患者在1、3和12个月时的剂量较低（P分别为0.048、0.03、0.041）。在影响他克莫司浓度的药物（如地尔硫䓬）的联合处方方面，各组之间无显著差异。急性排斥反应发作与CC、CT或TT基因型无关：优势比（OR）分别为0.517（95%置信区间[CI]，0.190 - 1.407；P = 0.192）；OR为1.558（95% CI，0.587 - 4.136；P = 0.372）；OR为1.346（95% CI，0.456 - 3.968；P = 0.590）。
结论
测定MDR1基因多态性可能有助于实现他克莫司血药浓度目标。
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