Influence of multidrug resistant gene polymorphisms and haplotype on blood concentration of tacrolimus in individuals in stable phases after renal transplantation
-
摘要: 目的 探讨MDR1 C1236T、G2677T/A和C3435T 基因多态性和单倍体对中国汉族肾移植术后稳定期患者他克莫司浓度/剂量比值的影响,为他克莫司个体化用药提供依据。 方法 采用PCR-基因测序法检测104例肾移植术后稳定期患者MDR1 C1236T、G2677T/A和C3435T 的基因多态性,采用均相酶免疫测定方法(EMIT法)测定他克莫司的谷浓度,比较不同基因型患者之间他克莫司血药浓度/(剂量×体质量)(C/D)比值。 结果 104例患者中,MDR1 C1236T、G2677T/A和C3435T突变频率分别为56.73%、55.77%和33.17%。MDR1 C3435T、MDR1 TTT单倍体与他克莫司C/D比值具有相关性(P<0.05)。CYP3A5*3*3患者中,MDR1 TTT单倍体与他克莫司C/D比值仍存在显著相关(P<0.05)。MDR1 C1236T、G2677T/A、CGC单倍体与他克莫司C/D比值无显著性差异(P>0.05)。 结论 MDR1 C3435T、MDR1 TTT单倍体与中国汉族肾移植术后稳定期患者他克莫司C/D比值具有显著相关性,是影响肾移植患者他克莫司浓度个体化差异的重要因素。Abstract: Objective To study the relevance between the polymorphisms and haplotype of multidrug resistant gene (MDR1) and the ratio of blood concentration/dosage in individuals treated by tacrolimus in stable phases post renal transplantation, and to provide data for personalized FK-506 administration. Methods The MDR1 C1236T, G2677T/A and C3435T genotypes of 104 renal transplantation patients were determined by PCR followed sequencing method. The blood concentration of tacrolimus was detected by EMIT method. The differences in concentration/ (dose×weight) (C/D) ratios were compared among all of the genotype groups treated by tacrolimus. Results In the 104 renal transplantation recipients, the frequency of MDR1 C1236T,G2677T/A and C3435T mutation alleles was 56.73%, 55.77% and 33.17%, respectively. A correlation was revealed among SNP of MDR1 C3435T, TTT haplotype and the C/D ratios (P<0.05). In patients of CYP3A5*3*3, A correlation was also found among TTT haplotype and the C/D ratios (P<0.05). No difference was found among the MDR1 C1236T, G2677T/A, CGC haplotype and the C/D ratios (P>0.05). Conclusion It is demonstrated that genetic polymorphisms of MDR1 C3435T and TTT haplotype are correlated with C/D ratio of tacrolimus in Chinese renal transplant patients in stable stage. These findings affect the dose-adjusted concentration of tacrolimus individually.
-
Key words:
- renal transplantation /
- tacrolimus /
- MDR1 /
- polymorphisms /
- haplotype
-
[1] Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study[J]. Lancet,2002,359:741-746. [2] Sandrini S, Aslam N, Tardanico R, et al. Tacrolimus versus cyclosporine for early steroid withdrawal after renal transplantation[J]. J Nephrol, 2012, 25(1):43-49. [3] Wallemacq P, Armstrong VW, Brunet M, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European Consensus Conference[J].Ther Drug Monit,2009,31(2):139-152. [4] Hoffmeyer S,Burk O,Von Richter O,et al. Functional polymorphisms of the human multidrug- resistance gene:multiple sequence variations and correlation of one allele with P- glycoprotein expression and activity in vivo[J]. Proc Natl Acad Sci (USA),2000,97(7):3473-3478. [5] 曾 明,邸晓辉,赵维娟,等. 五酯胶囊(片)对他克莫司血药浓度及药动学参数影响的Meta分析[J].解放军药学学报,2014,30(5):405-409. [6] 吴 雪,蔡 林,石姗平,等. 五酯胶囊对肾移植患者他克莫司血药浓度的影响[J].中国药房,2013,24(43):4094-4097. [7] 刘龙山,王长希,傅 茜,等. 五酯片用于肾移植患者对他克莫司药代动力学的影响及长期疗效观察[J]. 器官移植,2012,3(1):33-36. [8] 胡永芳,周宏灏. CYP3A4,CYP3A5和MDR1基因多态性对环抱素处置的影响[J].中国药理学通报,2005,21(3):257-261. [9] 李丹滢,方 芸. CYP3A4/5、ABCB1基因单倍型与中国肾移植患者他克莫司血药谷浓度相关性研究[J].药学与临床研究,2014,22(1):20-24. [10] Wu P, Ni X, Wang M, et al. Polymorphisms in CYP3A5*3 and MDR1, and haplotype modulate response to plasma levels of tacrolimus in Chinese renal transplant patients[J].Ann Transplant,2011, 16(1):54-60. [11] Glowacki F, Lionet A, Buob D, et al. CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on tacrolimus dose requirements and clinical outcome after renal transplantation[J]. Nephrol Dial Transplant,2011, 26(9):3046-3050. [12] Rong G, Jing L Deng L,et al.Influence of CYP3A5 and MDR1(ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in Chinese renal transplant recipients[J]. Transplant Proc,2010, 42(9):3455-3458. [13] Cusinato DA, Lacchini R, Romao EA, et al. Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients[J]. Br J Clin Pharmacol, 2014, 78(2):364-72. -
点击查看大图
计量
- 文章访问数: 3765
- HTML全文浏览量: 242
- PDF下载量: 427
- 被引次数: 0
下载:
