Application discussion of donor and recipient CYP3A5 genotyping in clinical individualized drug use of tacrolimus after operation in adult liver transplantation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YANG Bing ¹ , GUO Qingjun ² , TIAN Dazhi ² , LI Junjie ² , ZHANG Li ² , XIE Yan ² , CHEN Chiyi ² ,  JIANG Wentao ²

1. First Central Clinical College, Tianjin Medical University, Tianjin 300070, P. R. China;
2. Department of Liver Transplantation, Tianjin First Center Hospital; Key Laboratory for Critical Care Medicine of Ministry of Health; Tianjin Key Laboratory for Organ Transplantation; Tianjin Clinical Research Center for Organ Transplantation; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences; Tianjin 300192, P. R. China;

Corresponding author：

JIANG Wentao, Email: jiangwentao1974@163.com

Keywords：

liver transplantation; tacrolimus; cytochrome P4503A5; genotyping

DOI：

10.7507/1007-9424.201912120

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Objective To investigate the relationship between the CYP3A5 genotyping and the drug metabolism of tacrolimus after operation in adult liver transplantation.Methods Ninety-eight adult patients with liver transplantation in Tianjin First Center Hospital were selected as subjects. The blood samples of liver transplantation recipients and donor were collected before operation, and then tested the CYP3A5 genotyping by PCR method. The weekly body mass, tacrolimus dose, and drug valley concentration of the patients were monitored in 1, 2, 3, and 4 weeks after operation, to calculate the tacrolimus concentration/dose ratio. And then compared the effects of different genotyping of donor and receptors on tacrolimus concentration/dose ratio.Results In the CYP3A5 genotyping of 98 patients with liver transplantation and the corresponding donors, GG type was the most and AA type was the least, the distribution of alleles was in accordance with the genetic law, and the difference was not statistically significant (P>0.05). According to the donor genotype, the results showed that there was a significant correlation between tacrolimus concentration/dose ratio and donor or recipients CYP3A5 genotype at 1, 2, 3, and 4 weeks after liver transplantation, and there was significant difference among the three groups (P<0.05): GG>AG>AA. According to the combined grouping of donor and receptor genotype, the results showed that there was significant difference in tacrolimus concentration/dose ratio among A*/A*, A*/GG, GG/A*, and GG/GG group (P<0.05), while there was significant difference in tacrolimus concentration/dose ratio between GG/GG and A*/A* group (P<0.01), the tacrolimus concentration/dose ratio was highest in GG/GG group and lowest in A*/A* group.Conclusions The CYP3A5 genotyping of the recipient and donor can affect the blood concentration of tacrolimus after liver transplantation, and the CYP3A5 GG genotype is more likely to reach the target plasma concentration than the other genotypes, that the detection of donor and recipient CYP3A5 genotype in patients with liver transplantation can provide a reference for individualized treatment of tacrolimus after liver transplantation.

Citation： YANG Bing, GUO Qingjun, TIAN Dazhi, LI Junjie, ZHANG Li, XIE Yan, CHEN Chiyi, JIANG Wentao. Application discussion of donor and recipient CYP3A5 genotyping in clinical individualized drug use of tacrolimus after operation in adult liver transplantation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(9): 1084-1088. doi: 10.7507/1007-9424.201912120 Copy

1.	何晓顺, 杨安力. 肝脏移植实验研究的现状和展望. 中华实验外科杂志, 2012, 29(10): 1877-1879.
2.	刘其雨, 李立, 李晓延. CYP3A5 在肝移植术后他克莫司个体化治疗中的意义. 中国普外基础与临床杂志, 2010, 17(8): 795-797, 802.
3.	Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther, 2003, 74(3): 245-254.
4.	Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol, 2004, 44(2): 135-140.
5.	王毅, 赵闻雨, 张雷, 等. CYP3A5 基因多态性与肾移植受者术后早期他克莫司个体化应用的研究. 实用器官移植电子杂志, 2013, 1(1): 35-39.
6.	Macphee IA, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation, 2005, 79(4): 499-502.
7.	王剑. 相关基因的遗传多态性对他克莫司疗效的影响. 实用医药杂志, 2015, 32(1): 75-78.
8.	Masuda S, Inui K. An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol Ther, 2006, 112(1): 184-198.
9.	Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet, 2001, 27(4): 383-391.
10.	Berger FA, Mulder MB, Ten Bosch-Dijksman W, et al. Differences in CYP3A genotypes of a liver transplant recipient and the donor liver graft and adjustment of tacrolimus dose. Br J Clin Pharmacol, 2019, 85(8): 1852-1854.
11.	Ji E, Kim MG, Oh JM. CYP3A5 genotype-based model to predict tacrolimus dosage in the early postoperative period after living donor liver transplantation. Ther Clin Risk Manag, 2018, 14: 2119-2126.
12.	朱立勤, 章袁, 王楠, 等. 肝移植患者 CYP3A5 和 MDR1 基因多态性与他克莫司浓度/剂量比的关系. 中国新药杂志, 2015, 24(5): 545-549.
13.	王璐, 李宁, 卢实春, 等. 供受体 CYP3A5 基因多态性对成人肝移植术后他克莫司浓度/剂量比的影响. 实用器官移植电子杂志, 2013, 1(2): 88-94.
14.	沈丛欢, 夏强, 薛峰, 等. 肝移植受者 CYP3A5 基因多态性对他克莫司血药浓度与剂量比值的影响. 中华移植杂志: 电子版, 2013, 7(2): 66-70.
15.	Provenzani A, Notarbartolo M, Labbozzetta M, et al. The effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on tacrolimus dose requirements in Caucasian liver transplant patients. Ann Transplant, 2009, 14(1): 23-31.
16.	Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics, 2004, 14(3): 147-154.
17.	刘鸿凌. 细胞色素 P450 基因多态性对他克莫司临床应用的影响. 传染病信息, 2019, 32(3): 274-277.
18.	范皎, 胡梦, 陈香岭, 等. 免疫抑制剂的药物基因组学研究进展. 中华肾病研究电子杂志, 2018, 7(6): 280-284.
19.	李敏, 李峰, 高鑫. 基因多态性对他克莫司血药浓度影响的研究进展. 实用医药杂志, 2017, 34(2): 162-164.
20.	邱晓燕, 武卓, 徐璐扬, 等. CYP3A4、CYP3A5 和 CYP3A7 的基因多态性对中国汉族肾移植患者他克莫司药动学的影响. 药物流行病学杂志, 2019, 28(7): 451-455, 476.
21.	胡楠, 汤雨帆, 钱卿, 等. CYP3A5 和 ABCB1 基因多态性对肾移植患者术后初期他克莫司剂量、浓度及肾功能的影响. 中南药学, 2019, 17(4): 489-494.
22.	吕日新, 樊华. CYP3A5 基因型指导肝移植术后钙神经蛋白抑制剂的应用. 器官移植, 2019, 10(3): 283-287.
23.	Yanik MV, Seifert ME, Locke JE, et al. CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients. Pediatr Transplant, 2019, 23(5): e13494.
24.	王明睿, 翟秀宇, 王钢, 等. CYP3A5 基因多态性对肾移植术后患者他克莫司代谢的影响. 吉林大学学报: 医学版, 2018, 44(3): 537-542.
25.	Liu Y, Zhang T, Zhang X, et al. A new donors’ CYP3A5 and recipients’ CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients. Oncotarget, 2017, 8(41): 70250-70261.

1. 何晓顺, 杨安力. 肝脏移植实验研究的现状和展望. 中华实验外科杂志, 2012, 29(10): 1877-1879.
2. 刘其雨, 李立, 李晓延. CYP3A5 在肝移植术后他克莫司个体化治疗中的意义. 中国普外基础与临床杂志, 2010, 17(8): 795-797, 802.
3. Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther, 2003, 74(3): 245-254.
4. Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol, 2004, 44(2): 135-140.
5. 王毅, 赵闻雨, 张雷, 等. CYP3A5 基因多态性与肾移植受者术后早期他克莫司个体化应用的研究. 实用器官移植电子杂志, 2013, 1(1): 35-39.
6. Macphee IA, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation, 2005, 79(4): 499-502.
7. 王剑. 相关基因的遗传多态性对他克莫司疗效的影响. 实用医药杂志, 2015, 32(1): 75-78.
8. Masuda S, Inui K. An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol Ther, 2006, 112(1): 184-198.
9. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet, 2001, 27(4): 383-391.
10. Berger FA, Mulder MB, Ten Bosch-Dijksman W, et al. Differences in CYP3A genotypes of a liver transplant recipient and the donor liver graft and adjustment of tacrolimus dose. Br J Clin Pharmacol, 2019, 85(8): 1852-1854.
11. Ji E, Kim MG, Oh JM. CYP3A5 genotype-based model to predict tacrolimus dosage in the early postoperative period after living donor liver transplantation. Ther Clin Risk Manag, 2018, 14: 2119-2126.
12. 朱立勤, 章袁, 王楠, 等. 肝移植患者 CYP3A5 和 MDR1 基因多态性与他克莫司浓度/剂量比的关系. 中国新药杂志, 2015, 24(5): 545-549.
13. 王璐, 李宁, 卢实春, 等. 供受体 CYP3A5 基因多态性对成人肝移植术后他克莫司浓度/剂量比的影响. 实用器官移植电子杂志, 2013, 1(2): 88-94.
14. 沈丛欢, 夏强, 薛峰, 等. 肝移植受者 CYP3A5 基因多态性对他克莫司血药浓度与剂量比值的影响. 中华移植杂志: 电子版, 2013, 7(2): 66-70.
15. Provenzani A, Notarbartolo M, Labbozzetta M, et al. The effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on tacrolimus dose requirements in Caucasian liver transplant patients. Ann Transplant, 2009, 14(1): 23-31.
16. Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics, 2004, 14(3): 147-154.
17. 刘鸿凌. 细胞色素 P450 基因多态性对他克莫司临床应用的影响. 传染病信息, 2019, 32(3): 274-277.
18. 范皎, 胡梦, 陈香岭, 等. 免疫抑制剂的药物基因组学研究进展. 中华肾病研究电子杂志, 2018, 7(6): 280-284.
19. 李敏, 李峰, 高鑫. 基因多态性对他克莫司血药浓度影响的研究进展. 实用医药杂志, 2017, 34(2): 162-164.
20. 邱晓燕, 武卓, 徐璐扬, 等. CYP3A4、CYP3A5 和 CYP3A7 的基因多态性对中国汉族肾移植患者他克莫司药动学的影响. 药物流行病学杂志, 2019, 28(7): 451-455, 476.
21. 胡楠, 汤雨帆, 钱卿, 等. CYP3A5 和 ABCB1 基因多态性对肾移植患者术后初期他克莫司剂量、浓度及肾功能的影响. 中南药学, 2019, 17(4): 489-494.
22. 吕日新, 樊华. CYP3A5 基因型指导肝移植术后钙神经蛋白抑制剂的应用. 器官移植, 2019, 10(3): 283-287.
23. Yanik MV, Seifert ME, Locke JE, et al. CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients. Pediatr Transplant, 2019, 23(5): e13494.
24. 王明睿, 翟秀宇, 王钢, 等. CYP3A5 基因多态性对肾移植术后患者他克莫司代谢的影响. 吉林大学学报: 医学版, 2018, 44(3): 537-542.
25. Liu Y, Zhang T, Zhang X, et al. A new donors’ CYP3A5 and recipients’ CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients. Oncotarget, 2017, 8(41): 70250-70261.

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Application discussion of donor and recipient CYP3A5 genotyping in clinical individualized drug use of tacrolimus after operation in adult liver transplantation

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