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.	何曉順, 楊安力. 肝臟移植實驗研究的現狀和展望. 中華實驗外科雜志, 2012, 29(10): 1877-1879.
2.	劉其雨, 李立, 李曉延. CYP3A5 在肝移植術后他克莫司個體化治療中的意義. 中國普外基礎與臨床雜志, 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, 趙聞雨, 張雷, 等. CYP3A5 基因多態性與腎移植受者術后早期他克莫司個體化應用的研究. 實用器官移植電子雜志, 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.	王劍. 相關基因的遺傳多態性對他克莫司療效的影響. 實用醫藥雜志, 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 基因多態性與他克莫司濃度/劑量比的關系. 中國新藥雜志, 2015, 24(5): 545-549.
13.	王璐, 李寧, 盧實春, 等. 供受體 CYP3A5 基因多態性對成人肝移植術后他克莫司濃度/劑量比的影響. 實用器官移植電子雜志, 2013, 1(2): 88-94.
14.	沈叢歡, 夏強, 薛峰, 等. 肝移植受者 CYP3A5 基因多態性對他克莫司血藥濃度與劑量比值的影響. 中華移植雜志: 電子版, 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.	劉鴻凌. 細胞色素 P450 基因多態性對他克莫司臨床應用的影響. 傳染病信息, 2019, 32(3): 274-277.
18.	范皎, 胡夢, 陳香嶺, 等. 免疫抑制劑的藥物基因組學研究進展. 中華腎病研究電子雜志, 2018, 7(6): 280-284.
19.	李敏, 李峰, 高鑫. 基因多態性對他克莫司血藥濃度影響的研究進展. 實用醫藥雜志, 2017, 34(2): 162-164.
20.	邱曉燕, 武卓, 徐璐揚, 等. CYP3A4、CYP3A5 和 CYP3A7 的基因多態性對中國漢族腎移植患者他克莫司藥動學的影響. 藥物流行病學雜志, 2019, 28(7): 451-455, 476.
21.	胡楠, 湯雨帆, 錢卿, 等. CYP3A5 和 ABCB1 基因多態性對腎移植患者術后初期他克莫司劑量、濃度及腎功能的影響. 中南藥學, 2019, 17(4): 489-494.
22.	呂日新, 樊華. CYP3A5 基因型指導肝移植術后鈣神經蛋白抑制劑的應用. 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, 王鋼, 等. CYP3A5 基因多態性對腎移植術后患者他克莫司代謝的影響. 吉林大學學報: 醫學版, 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. 何曉順, 楊安力. 肝臟移植實驗研究的現狀和展望. 中華實驗外科雜志, 2012, 29(10): 1877-1879.
2. 劉其雨, 李立, 李曉延. CYP3A5 在肝移植術后他克莫司個體化治療中的意義. 中國普外基礎與臨床雜志, 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, 趙聞雨, 張雷, 等. CYP3A5 基因多態性與腎移植受者術后早期他克莫司個體化應用的研究. 實用器官移植電子雜志, 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. 王劍. 相關基因的遺傳多態性對他克莫司療效的影響. 實用醫藥雜志, 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 基因多態性與他克莫司濃度/劑量比的關系. 中國新藥雜志, 2015, 24(5): 545-549.
13. 王璐, 李寧, 盧實春, 等. 供受體 CYP3A5 基因多態性對成人肝移植術后他克莫司濃度/劑量比的影響. 實用器官移植電子雜志, 2013, 1(2): 88-94.
14. 沈叢歡, 夏強, 薛峰, 等. 肝移植受者 CYP3A5 基因多態性對他克莫司血藥濃度與劑量比值的影響. 中華移植雜志: 電子版, 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. 劉鴻凌. 細胞色素 P450 基因多態性對他克莫司臨床應用的影響. 傳染病信息, 2019, 32(3): 274-277.
18. 范皎, 胡夢, 陳香嶺, 等. 免疫抑制劑的藥物基因組學研究進展. 中華腎病研究電子雜志, 2018, 7(6): 280-284.
19. 李敏, 李峰, 高鑫. 基因多態性對他克莫司血藥濃度影響的研究進展. 實用醫藥雜志, 2017, 34(2): 162-164.
20. 邱曉燕, 武卓, 徐璐揚, 等. CYP3A4、CYP3A5 和 CYP3A7 的基因多態性對中國漢族腎移植患者他克莫司藥動學的影響. 藥物流行病學雜志, 2019, 28(7): 451-455, 476.
21. 胡楠, 湯雨帆, 錢卿, 等. CYP3A5 和 ABCB1 基因多態性對腎移植患者術后初期他克莫司劑量、濃度及腎功能的影響. 中南藥學, 2019, 17(4): 489-494.
22. 呂日新, 樊華. CYP3A5 基因型指導肝移植術后鈣神經蛋白抑制劑的應用. 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, 王鋼, 等. CYP3A5 基因多態性對腎移植術后患者他克莫司代謝的影響. 吉林大學學報: 醫學版, 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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