CYP3A5基因型与肾移植患者他克莫司血药浓度关系的系统评价_《中国循证医学杂志》

作者：

付生军 ^1,2,3,4 , 刘静 ⁵ , 李涛 ^1,2,3,4 , 王志平 ^1,2,3,4 ,  杨立 ^1,2,3,4

1. 兰州大学泌尿外科研究所（兰州 730030）；2. 兰州大学第二医院泌尿外科（兰州 730030）；3 甘肃省泌尿系统疾病临床医学中心（兰州 730030）；4. 甘肃省泌尿系统疾病研究重点实验室（兰州 730030）；5. 兰州大学第二医院肝病科(兰州 730030）;

关键词：

他克莫司 CYP3A5 Meta分析系统评价

DOI：

10.7507/1672-2531.20130247

视频：

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摘要 全文 图表 视频 参考文献 施引文献 补充材料

目的　系统评价CYP3A5基因型与肾移植术后他克莫司（FK506）血药浓度的关系。
方法　计算机检索PubMed（1966.1～2013.7）、Sciverse（1823.1～2013.7）、The Cochrane Library（2013年第7期）、CNKI（1994.1～2013.7）、VIP（1989.1-2013.7）、CBM（1978.1～2013.7）及WanFang Data（1995.1～2013.7），查找关于CYP3A5基因型与肾移植术后他克莫司（FK506）血药浓度/剂量关系的文献。根据纳入与排除标准筛选文献、提取资料和评价质量后，采用RevMan 5.2软件进行Meta分析。
结果　共纳入12篇文献，包含956例对象。Meta分析结果显示：在肾移植术后7天［MD=54.61，95%CI（–67.67，–41.54），P lt;0.000 01］、1个月［MD= –74.84，95%CI（–83.39，–66.29），P lt;0.000 01］、3个月［MD= –96.09，95%CI（–107.55，–84.64），P lt;0.000 01］、6个月［MD= –107.30，95%CI（–125.65，–88.95），P lt;0.000 01］和1年［MD= –78.32，95%CI（–123.02，–33.61），P=0.000 6］，携带CYP3A5 3/3基因型患者的FK506 血药浓度/剂量值明显较携带其他基因型患者高；而携带1/1患者的FK506 血药浓度/剂量值较低。
结论　肾移植术后FK506血药浓度/剂量值与CYP3A5基因型相关。因此在肾移植术后应用FK506作为免疫抑制治疗时，有必要对患者进行CYP3A5基因型检测，以指导临床治疗。

引用本文： 付生军,刘静,李涛,王志平,杨立. CYP3A5基因型与肾移植患者他克莫司血药浓度关系的系统评价. 中国循证医学杂志, 2013, 13(12): 1440-1445. doi: 10.7507/1672-2531.20130247 复制

1. 侯明明, 高菲, 宋洪涛. 肾移植术后2组免疫抑制剂用药方案的成本一效果分析. 中国药房, 2009, 20(5): 331.

2. 陈伟, 胡志德, 吴丽娟, 等. mdr1基因C3435T多态性与口服FK506后血药浓度关系的实验研究. 第三军医大学学报, 2006, 28(19): 1971-1972.

3. Ninova D, Covarrubias M, Rea DJ, et al. Acute nephrotoxicity of tacrolimus and sirolimus in renal isografts: differential intragraft expression of transforming growth factor-beta1 and alpha-smooth muscle actin. Transplantation, 2004, 78(3): 338-434.

4. 张海燕, 张小明, 吴小丽, 等. CYP3A5基因多态性对中国肾移植受者他克莫司血药浓度和疗效的影响. 器官移植, 2011, 2(6): 328-331.

5. Miao LY, Huang CR, Hou JQ, et al. Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients. Biopharm Drug Dispos, 2008, 29(1): 1-5.

6. Chen JS, Li LS, Cheng DR, et al. Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus. Transplant Proc, 2009, 41(5): 1557-1561.

7. Kim IW, Noh H, Ji E, et al. Identification of factors affecting tacrolimus level and 5-year clinical outcome in kidney transplant patients. Basic Clin Pharmacol Toxicol, 2012, 111(4): 217-223.

8. Singh R, Srivastava A, Kapoor R, et al. Impact of CYP3A5 and CYP3A4genepolymorphisms on doserequirement of calcineurininhibitors, cyclosporine and tacrolimus, in renalallograftrecipients of NorthIndia. Naunyn Schmiedebergs Arch Pharmacol, 2009, 380(2): 169-177.

9. Cho JH, Yoon YD, Park JY, et al. Impact of cytochrome P450 3A and ATP-binding cassette subfamily B member 1 polymorphisms on tacrolimus dose-adjusted trough concentrations among Korean renal transplant recipients. Transplant Proc, 2012, 44(1): 109-114.

10. Gervasini G, Garcia M, Macias RM, et al. Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation. Transpl Int, 2012, 25(4): 471-480.

11. Provenzani A, Notarbartolo M, Labbozzetta M, et al. Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients. Int J Mol Med, 2011, 28(6): 1093-1102.

12. Zhang X, Liu ZH, Zheng JM, et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant, 2005, 19(5): 638-643.

13. Li L, Li CJ, Zheng L, et al. Tacrolimusdosing in Chineserenal transplantrecipients: a population-basedpharmacogeneticsstudy. Eur J Clin Pharmacol, 2011, 67(8): 787-795.

14. Ferraris JR, Argibay PF, Costa L, et al. Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids. Pediatr Transplant, 2011, 15(5): 525-532.

15. 孙华宾, 刘燕, 王道虎. 肾移植受者CYP3A5基因多态性对他可莫司代谢的影响. 国际医药卫生导报, 2009, 15(3): 5-7.

16. Zhang G, Zhang Y, Su Z. CYPSI: a structure-basedinterface for cytochromeP450s and ligands in Arabidopsisthaliana. BMC Bioinformatics, 2012, 13: 332.

17. 王若伦, 叶晓光, 叶丽卡, 等. 细胞色素P450 3A5基因多态性的研究进展. 中国药房, 2008, 19(4): 304-306.

18. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of po1ymorphic CYP3A5 expression. Nat Genet, 2001, 27(4): 383-391.

19. 孙阳洋, 何军, 邱桥成, 等. 细胞色素P4503A亚家族多肽5基因多态性对肾移植患者术后他克莫司血药浓度的影响. 中华实验外科杂志, 2013, 4(4): 848-851.

20. Thervet E, Anglicheau D, King B, et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation, 2003, 76(8): 1233-1235.

21. 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. Ann Transplant, 2011, 16(1): 54-60.

22. Hirano K, Naito T, Mino Y, et al. Impact of CYP3A5 genetic polymorphism on cross-reactivity in tacrolimus chemiluminescent immunoassay in kidney transplant recipients. Clin Chim Acta, 2012, 414: 120-124.

23. Pashaee N, Bouamar R, Hesselink DA, et al. CYP3A5 genotype is not related to the intrapatient variability of tacrolimus clearance. Ther Drug Monit, 2011, 33(3): 369-371.

24. Kamdem LK, Streit F, Zanger UM, et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem, 2005, 51(8): 1374-1381.

25. Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol, 2008, 103(6): 546-552.

1. 侯明明, 高菲, 宋洪涛. 肾移植术后2组免疫抑制剂用药方案的成本一效果分析. 中国药房, 2009, 20(5): 331.

2. 陈伟, 胡志德, 吴丽娟, 等. mdr1基因C3435T多态性与口服FK506后血药浓度关系的实验研究. 第三军医大学学报, 2006, 28(19): 1971-1972.

3. Ninova D, Covarrubias M, Rea DJ, et al. Acute nephrotoxicity of tacrolimus and sirolimus in renal isografts: differential intragraft expression of transforming growth factor-beta1 and alpha-smooth muscle actin. Transplantation, 2004, 78(3): 338-434.

4. 张海燕, 张小明, 吴小丽, 等. CYP3A5基因多态性对中国肾移植受者他克莫司血药浓度和疗效的影响. 器官移植, 2011, 2(6): 328-331.

5. Miao LY, Huang CR, Hou JQ, et al. Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients. Biopharm Drug Dispos, 2008, 29(1): 1-5.

6. Chen JS, Li LS, Cheng DR, et al. Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus. Transplant Proc, 2009, 41(5): 1557-1561.

7. Kim IW, Noh H, Ji E, et al. Identification of factors affecting tacrolimus level and 5-year clinical outcome in kidney transplant patients. Basic Clin Pharmacol Toxicol, 2012, 111(4): 217-223.

8. Singh R, Srivastava A, Kapoor R, et al. Impact of CYP3A5 and CYP3A4genepolymorphisms on doserequirement of calcineurininhibitors, cyclosporine and tacrolimus, in renalallograftrecipients of NorthIndia. Naunyn Schmiedebergs Arch Pharmacol, 2009, 380(2): 169-177.

9. Cho JH, Yoon YD, Park JY, et al. Impact of cytochrome P450 3A and ATP-binding cassette subfamily B member 1 polymorphisms on tacrolimus dose-adjusted trough concentrations among Korean renal transplant recipients. Transplant Proc, 2012, 44(1): 109-114.

10. Gervasini G, Garcia M, Macias RM, et al. Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation. Transpl Int, 2012, 25(4): 471-480.

11. Provenzani A, Notarbartolo M, Labbozzetta M, et al. Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients. Int J Mol Med, 2011, 28(6): 1093-1102.

12. Zhang X, Liu ZH, Zheng JM, et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant, 2005, 19(5): 638-643.

13. Li L, Li CJ, Zheng L, et al. Tacrolimusdosing in Chineserenal transplantrecipients: a population-basedpharmacogeneticsstudy. Eur J Clin Pharmacol, 2011, 67(8): 787-795.

14. Ferraris JR, Argibay PF, Costa L, et al. Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids. Pediatr Transplant, 2011, 15(5): 525-532.

15. 孙华宾, 刘燕, 王道虎. 肾移植受者CYP3A5基因多态性对他可莫司代谢的影响. 国际医药卫生导报, 2009, 15(3): 5-7.

16. Zhang G, Zhang Y, Su Z. CYPSI: a structure-basedinterface for cytochromeP450s and ligands in Arabidopsisthaliana. BMC Bioinformatics, 2012, 13: 332.

17. 王若伦, 叶晓光, 叶丽卡, 等. 细胞色素P450 3A5基因多态性的研究进展. 中国药房, 2008, 19(4): 304-306.

18. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of po1ymorphic CYP3A5 expression. Nat Genet, 2001, 27(4): 383-391.

19. 孙阳洋, 何军, 邱桥成, 等. 细胞色素P4503A亚家族多肽5基因多态性对肾移植患者术后他克莫司血药浓度的影响. 中华实验外科杂志, 2013, 4(4): 848-851.

20. Thervet E, Anglicheau D, King B, et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation, 2003, 76(8): 1233-1235.

21. 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. Ann Transplant, 2011, 16(1): 54-60.

22. Hirano K, Naito T, Mino Y, et al. Impact of CYP3A5 genetic polymorphism on cross-reactivity in tacrolimus chemiluminescent immunoassay in kidney transplant recipients. Clin Chim Acta, 2012, 414: 120-124.

23. Pashaee N, Bouamar R, Hesselink DA, et al. CYP3A5 genotype is not related to the intrapatient variability of tacrolimus clearance. Ther Drug Monit, 2011, 33(3): 369-371.

24. Kamdem LK, Streit F, Zanger UM, et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem, 2005, 51(8): 1374-1381.

25. Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol, 2008, 103(6): 546-552.

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亚洲健康人群CYP2C19等位基因发生率的合并分析

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1资料与方法

1.1一般资料

1.2方法

1.3察指标和判定标准

1.4统计学方法

2结果

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3讨论

《中国循证医学杂志》

CYP3A5基因型与肾移植患者他克莫司血药浓度关系的系统评价

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1.	侯明明, 高菲, 宋洪涛. 肾移植术后2组免疫抑制剂用药方案的成本一效果分析. 中国药房, 2009, 20(5): 331.
2.	陈伟, 胡志德, 吴丽娟, 等. mdr1基因C3435T多态性与口服FK506后血药浓度关系的实验研究. 第三军医大学学报, 2006, 28(19): 1971-1972.
3.	Ninova D, Covarrubias M, Rea DJ, et al. Acute nephrotoxicity of tacrolimus and sirolimus in renal isografts: differential intragraft expression of transforming growth factor-beta1 and alpha-smooth muscle actin. Transplantation, 2004, 78(3): 338-434.
4.	张海燕, 张小明, 吴小丽, 等. CYP3A5基因多态性对中国肾移植受者他克莫司血药浓度和疗效的影响. 器官移植, 2011, 2(6): 328-331.
5.	Miao LY, Huang CR, Hou JQ, et al. Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients. Biopharm Drug Dispos, 2008, 29(1): 1-5.
6.	Chen JS, Li LS, Cheng DR, et al. Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus. Transplant Proc, 2009, 41(5): 1557-1561.
7.	Kim IW, Noh H, Ji E, et al. Identification of factors affecting tacrolimus level and 5-year clinical outcome in kidney transplant patients. Basic Clin Pharmacol Toxicol, 2012, 111(4): 217-223.
8.	Singh R, Srivastava A, Kapoor R, et al. Impact of CYP3A5 and CYP3A4genepolymorphisms on doserequirement of calcineurininhibitors, cyclosporine and tacrolimus, in renalallograftrecipients of NorthIndia. Naunyn Schmiedebergs Arch Pharmacol, 2009, 380(2): 169-177.
9.	Cho JH, Yoon YD, Park JY, et al. Impact of cytochrome P450 3A and ATP-binding cassette subfamily B member 1 polymorphisms on tacrolimus dose-adjusted trough concentrations among Korean renal transplant recipients. Transplant Proc, 2012, 44(1): 109-114.
10.	Gervasini G, Garcia M, Macias RM, et al. Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation. Transpl Int, 2012, 25(4): 471-480.
11.	Provenzani A, Notarbartolo M, Labbozzetta M, et al. Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients. Int J Mol Med, 2011, 28(6): 1093-1102.
12.	Zhang X, Liu ZH, Zheng JM, et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant, 2005, 19(5): 638-643.
13.	Li L, Li CJ, Zheng L, et al. Tacrolimusdosing in Chineserenal transplantrecipients: a population-basedpharmacogeneticsstudy. Eur J Clin Pharmacol, 2011, 67(8): 787-795.
14.	Ferraris JR, Argibay PF, Costa L, et al. Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids. Pediatr Transplant, 2011, 15(5): 525-532.
15.	孙华宾, 刘燕, 王道虎. 肾移植受者CYP3A5基因多态性对他可莫司代谢的影响. 国际医药卫生导报, 2009, 15(3): 5-7.
16.	Zhang G, Zhang Y, Su Z. CYPSI: a structure-basedinterface for cytochromeP450s and ligands in Arabidopsisthaliana. BMC Bioinformatics, 2012, 13: 332.
17.	王若伦, 叶晓光, 叶丽卡, 等. 细胞色素P450 3A5基因多态性的研究进展. 中国药房, 2008, 19(4): 304-306.
18.	Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of po1ymorphic CYP3A5 expression. Nat Genet, 2001, 27(4): 383-391.
19.	孙阳洋, 何军, 邱桥成, 等. 细胞色素P4503A亚家族多肽5基因多态性对肾移植患者术后他克莫司血药浓度的影响. 中华实验外科杂志, 2013, 4(4): 848-851.
20.	Thervet E, Anglicheau D, King B, et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation, 2003, 76(8): 1233-1235.
21.	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. Ann Transplant, 2011, 16(1): 54-60.
22.	Hirano K, Naito T, Mino Y, et al. Impact of CYP3A5 genetic polymorphism on cross-reactivity in tacrolimus chemiluminescent immunoassay in kidney transplant recipients. Clin Chim Acta, 2012, 414: 120-124.
23.	Pashaee N, Bouamar R, Hesselink DA, et al. CYP3A5 genotype is not related to the intrapatient variability of tacrolimus clearance. Ther Drug Monit, 2011, 33(3): 369-371.
24.	Kamdem LK, Streit F, Zanger UM, et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem, 2005, 51(8): 1374-1381.
25.	Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol, 2008, 103(6): 546-552.

《中国循证医学杂志》

CYP3A5基因型与肾移植患者他克莫司血药浓度关系的系统评价

摘要 全文 图表 视频 参考文献 施引文献 补充材料

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