Correlation between CYP3A5 Genotypes and Blood Levels of Tacrolimus in Renal Transplant Recipients: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

FU Shengjun ^1,2,3,4 , LIU Jing ⁵ , LI Tao ^1,2,3,4 , WANG Zhiping ^1,2,3,4 ,  YANG Li ^1,2,3,4

1. Urology Research Institute of Lanzhou University, Lanzhou 730030, China; 2. Department of Urology, The Second Hospital of Lanzhou University, Lanzhou 730030, China;3. Nephro-Urological Clinical Center of Gansu Province, Lanzhou 730030, China;4. Key Laboratory of Urological Disease of Gansu Province, Lanzhou 730030, China;5. Department of Liver Disease, The Second Hospital of Lanzhou University, Lanzhou 730030, China;

Corresponding author：

YANG Li, Email: yuze250@163.com

Keywords：

Tacrolimus; CYP3A5; Meta-analysis; Systematic review

DOI：

10.7507/1672-2531.20130247

Video：

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Objective 　To systematically review the correlation between CYP3A5 genotypes and blood levels of tacrolimus (FK506) in renal transplant recipients.
Methods 　Such databases as PubMed (January 1966 to July 2013), Sciverse (January 1823 to July 2013), The Cochrane Library (Issue 7, 2013), CNKI (January 1994 to July 2013), VIP (January 1989 to July 2013), CBM (January 1978 to July 2013) and WanFang Data (January 1995 to July 2013) were electronically searched for studies about the correlation between CYP3A5 genotypes and FK506 (blood concentration/dose-respones relationship) in renal transplant recipients. According to the inclusion and exclusion criteria, literature was screened, data were extracted, and the methodological quality of included studies was also assessed. Then, meta-analysis was performed using RevMan 5.2 software.
Results 　A total of 12 articles involving 956 patients were included. The results of meta-analysis showed that, after renal transplantation, there was a high dose-adjusted concentration of CYP3A5 3/3 carriers on the 7th day (MD= 54.61, 95%CI –67.67 to –41.54, P lt;0.000 01), in the 1st month (MD= –74.84, 95%CI –83.39 to –66.29, P lt;0.000 01), in the 3rd month (MD= –96.09, 95%CI –107.55 to –84.64, P lt;0.000 01), in the 6th month (MD= –107.30, 95%CI –125.65 to –88.95, P lt;0.000 01), and in the 1st year (MD= –78.32, 95%CI –123.02 to –33.61, P=0.000 6). The dose-adjusted concentration of FK506 in CYP3A5 3/3 patients was higher than the other genotypes, while the dose-adjusted concentration of FK506 in CYP3A5 1/1 patients was low.
Conclusion 　The blood concentration as well as dose-respones relationship of FK506 are associated with CYP3A5 genotype in renal transplant recipients. We propose that patients with renal transplantation should receive CYP3A5 genotypes test to determine the use of FK506 as an immunosuppressant, so as to guide its clinical application.

Citation： FU Shengjun,LIU Jing,LI Tao,WANG Zhiping,YANG Li. Correlation between CYP3A5 Genotypes and Blood Levels of Tacrolimus in Renal Transplant Recipients: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2013, 13(12): 1440-1445. doi: 10.7507/1672-2531.20130247 Copy

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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Correlation between CYP3A5 Genotypes and Blood Levels of Tacrolimus in Renal Transplant Recipients: A Systematic Review

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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.