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根据CYP3A5*1基因多态性指导肝移植术后他克莫司个体化用药的前瞻性对照研究

何莉 栗光明 林栋栋 刘晋宁 王鑫 王璐

何莉, 栗光明, 林栋栋, 等. 根据CYP3A5*1基因多态性指导肝移植术后他克莫司个体化用药的前瞻性对照研究[J]. 器官移植, 2020, 11(4): 455-460. doi: 10.3969/j.issn.1674-7445.2020.04.005
引用本文: 何莉, 栗光明, 林栋栋, 等. 根据CYP3A5*1基因多态性指导肝移植术后他克莫司个体化用药的前瞻性对照研究[J]. 器官移植, 2020, 11(4): 455-460. doi: 10.3969/j.issn.1674-7445.2020.04.005
He Li, Li Guangming, Lin Dongdong, et al. Individualized medication of tacrolimus after liver transplantation guided by CYP3A5*1 gene polymorphisms: a prospective controlled study[J]. ORGAN TRANSPLANTATION, 2020, 11(4): 455-460. doi: 10.3969/j.issn.1674-7445.2020.04.005
Citation: He Li, Li Guangming, Lin Dongdong, et al. Individualized medication of tacrolimus after liver transplantation guided by CYP3A5*1 gene polymorphisms: a prospective controlled study[J]. ORGAN TRANSPLANTATION, 2020, 11(4): 455-460. doi: 10.3969/j.issn.1674-7445.2020.04.005

根据CYP3A5*1基因多态性指导肝移植术后他克莫司个体化用药的前瞻性对照研究

doi: 10.3969/j.issn.1674-7445.2020.04.005
基金项目: 

首都临床特色应用研究与成果推广 Z171100001017035

详细信息
    作者简介:

    何莉,女,1989年生,硕士,主治医师,研究方向为供体器官维护及肝移植围手术期管理,Email:helily0029@163.com

    通讯作者:

    王璐,女,1982年生,博士,主任医师,研究方向为肝移植术后随访管理,Email:p-p@yeah.net

  • 中图分类号: R617

Individualized medication of tacrolimus after liver transplantation guided by CYP3A5*1 gene polymorphisms: a prospective controlled study

More Information
  • 摘要:   目的  评价基于细胞色素P450(CYP)3A5*1基因多态性指导肝移植术后他克莫司(FK506)个体化用药的安全性和有效性。  方法  分析连续入组的100例首次行肝移植术受者的临床资料,并随机分为实验组和对照组,每组各50例。实验组术前对供、受者进行CYP3A5基因检测,并根据CYP3A5*1基因型确定FK506用药方案。观察术后7、14、28 d以及3、6、9、12个月两组受者FK506目标血药浓度达标率、肝功能恢复正常率以及随访过程中FK506调整用量次数。记录两组受者1年移植物存活率,及急性排斥反应、感染、急性肾损伤、消化道症状、新发高血压、新发糖尿病、感冒、皮疹等并发症的发生率。  结果  两组受者术后7、14 d FK506目标血药浓度达标率比较,差异均有统计学意义(均为P < 0.05)。两组术后28 d及3、6、9、12个月FK506目标血药浓度达标率及术后7个观察时间点肝功能恢复正常率比较,差异均无统计学意义(均为P > 0.05)。两组受者随访期间FK506剂量调整次数比较,差异有统计学意义(P=0.021)。两组受者术后及随访期间1年移植物存活率和并发症发生率比较,差异均无统计学意义(均为P > 0.05)。  结论  根据CYP3A5*1基因多态性指导肝移植术后FK506个体化用药是安全的,能在术后早期提高受者FK506目标血药浓度达标率,并且可以有效减少随访期间药量调整次数。

     

  • 表  1  两组受者术后1年内各时间点FK506目标血药浓度达标率

    Table  1.   Compliance rate of FK506 target blood concentration at various time points within 1 year after operation in both groups of recipients[n(%)]

    术后时间 对照组
    n=50)
    实验组
    n=50)
    χ2 P
    7 d 20(40) 32(64) 5.769 0.016
    14 d 27(54) 39(78) 6.417 0.011
    28 d 36(72) 43(86) 2.954 0.086
    3个月 38(76) 41(82) 0.542 0.461
    6个月 41(82) 43(86) 0.298 0.585
    9个月 44(88) 41(82) 0.706 0.401
    12个月 44(88) 45(90) 0.102 0.749
    下载: 导出CSV

    表  2  两组受者术后1年内各时间点肝功能恢复正常率

    Table  2.   The recovery rate of liver function at various time points within 1 year after operation in both groups of recipients[n(%)]

    术后时间 对照组
    n=50)
    实验组
    n=50)
    χ2 P
    7 d 5(10) 8(16) 0.796 0.372
    14 d 11(22) 17(34) 1.786 0.181
    28 d 20(40) 27(54) 1.967 0.161
    3个月 35(70) 40(80) 1.333 0.248
    6个月 43(86) 44(88) 0.088 0.766
    9个月 42(84) 43(86) 0.078 0.779
    12个月 44(88) 43(86) 0.088 0.766
    下载: 导出CSV

    表  3  两组FK506药物安全性观察指标比较

    Table  3.   Comparison of FK506 drug safety observation indexes between two groups [n(%)]

    观察指标 对照组
    n=50)
    实验组
    n=50)
    χ2 P
    急性排斥反应 5(10) 3(6) 0.543 0.461
    感染 15(30) 13(26) 0.198 0.656
    急性肾损伤 22(44) 25(50) 0.361 0.548
    新发糖尿病 18(36) 15(30) 0.407 0.523
    新发高血压 17(34) 19(38) 0.174 0.677
    腹泻、恶心 4(8) 6(12) 0.444 0.505
    皮疹 0(0) 1(2) 0.990 0.320
    感冒 7(14) 9(18) 0.798 0.585
    移植物存活1年 46(92) 45(90) 0.122 0.727
    下载: 导出CSV
  • [1] HRYNIEWIECKA E, ZEGARSKA J, ZOCHOWSKA D, et al. Lack of relationship between renal function and genetic variants of CYP3A4, CYP3A5, MDR1, MRP2, UGT1A9, UGT1A8, and UGT2B7 in patients after liver transplantation in a 2-year follow-up[J]. Transplant Proc, 2020, DOI: 10.1016/j.transproceed.2020.01.096[Epubahead of print].
    [2] TOGASHI J, AKAMASTU N, KOKUDO N. Living donor liver transplantation for hepatocellular carcinoma at the University of Tokyo Hospital[J]. Hepatobiliary Surg Nutr, 2016, 5(5):399-407. doi: 10.21037/hbsn.2016.08.05
    [3] JAIN A, DOPPALAPUDI S, DOMB AJ, et al. Tacrolimus and curcumin co-loaded liposphere gel: synergistic combination towards management of psoriasis[J]. J Control Release, 2016, 243:132-145. DOI: 10.1016/j.jconrel. 2016.10.004.
    [4] KUYPERS DR. "What do we know about tacrolimus pharmacogenetics in transplant recipients?"[J]. Pharmacogenomics, 2018, 19(7):593-597. DOI: 10.2217/pgs-2018-0035.
    [5] DEBETTE-GRATIEN M, WOILLARD JB, PICARD N, et al. Influence of donor and recipient CYP3A4, CYP3A5, and ABCB1 genotypes on clinical outcomes and nephrotoxicity in liver transplant recipients[J]. Transplantation, 2016, 100(10):2129-2137. doi: 10.1097/TP.0000000000001394
    [6] WANG YQ, WANG CH, ZHANG JH. Association between CYP3A5 polymorphisms and the risk of adverse events in patients undergoing clopidogrel therapy: Meta-analysis[J]. Thromb Res, 2016, 147:1-6. DOI: 10.1016/j.thromres.2016.09.016.
    [7] CAMPAGNE O, MAGER DE, TORNATORE KM. Population pharmacokinetics of tacrolimus in transplant recipients: what did we learn about sources of interindividual variabilities?[J]. J Clin Pharmacol, 2019, 59(3):309-325. DOI: 10.1002/jcph.1325.
    [8] 江佳, 刘俊, 汪琳, 等.异基因造血干细胞移植受者CYP3A4及CYP3A5基因多态性对他克莫司血药浓度及疗效的影响[J].安徽医药, 2018, 22(2):344-347.DOI: 10.3969/j.issn.1009-6469.2018.02.040.

    JIANG J, LIU J, WANG L, et al. Effect of CYP3A4 and CYP3A5 genetic polymorphism on blood concentration and efficacy of tacrolimus in patients with allogeneic hematopoietic stem cell transplantation[J]. Anhui Med Pharm J, 2018, 22(2):344-347. DOI: 10.3969/j.issn.1009-6469. 2018.02.040.
    [9] CZERWIŃSKI M, AMUNOM I, PIRYATINSKY V, et al. Direct and cytokine-mediated effects of albumin-fused growth hormone, TV-1106, on CYP enzyme expression in human hepatocytes in vitro[J]. Pharmacol Res Perspect, 2018, 6(3):e00397. DOI: 10.1002/prp2.397.
    [10] CHAN SW, XIAO Y, HU M, et al. Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6β-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese[J]. J Clin Pharm Ther, 2016, 41(5):552-558. DOI: 10.1111/jcpt.12433.
    [11] MIYATA Y, AKAMATSU N, SUGAWARA Y, et al. Pharmacokinetics of a once-daily dose of tacrolimus early after liver transplantation: with special reference to CYP3A5 and ABCB1 single nucleotide polymorphisms[J]. Ann Transplant, 2016, 21:491-499. doi: 10.12659/AOT.898358
    [12] ABO EL FOTOH WM, ABD EL NABY SA, HABIB MS, et al. The potential implication of SCN1A and CYP3A5 genetic variants on antiepileptic drug resistance among Egyptian epileptic children[J]. Seizure, 2016, 41:75-80. DOI: 10.1016/j.seizure.2016.07.005.
    [13] ITOHARA K, YANO I, TSUZUKI T, et al. A minimal physiologically-based pharmacokinetic model for tacrolimus in living-donor liver transplantation: perspectives related to liver regeneration and the cytochrome P450 3A5 (CYP3A5) genotype[J]. CPT Pharmacometrics Syst Pharmacol, 2019, 8(8):587-595. DOI: 10.1002/psp4.12420.
    [14] ADEAGBO BA, BOLAJI OO, OLUGBADE TA, et al. Influence of CYP3A5*3 and ABCB1 C3435T on clinical outcomes and trough plasma concentrations of imatinib in Nigerians with chronic myeloid leukaemia[J]. J Clin Pharm Ther, 2016, 41(5):546-551. DOI: 10.1111/jcpt.12424.
    [15] MIYAUCHI E, TACHIKAWA M, DECLÈVES X, et al. Quantitative atlas of cytochrome P450, UDP-glucuronosyltransferase, and transporter proteins in jejunum of morbidly obese subjects[J]. Mol Pharm, 2016, 13(8):2631-2640. DOI: 10.1021/acs.molpharmaceut. 6b00085.
    [16] KUEHL P, ZHANG J, LIN Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression[J]. Nat Genet, 2001, 27(4):383-391. doi: 10.1038/86882
    [17] DENG R, LIAO Y, LI Y, et al. Association of CYP3A5, CYP2C8, and ABCB1 polymorphisms with early renal injury in Chinese liver transplant recipients receiving tacrolimus[J]. Transplant Proc, 2018, 50(10):3258-3265. DOI: 10.1016/j.transproceed.2018.06.040.
    [18] HENDERSON LM, CLAW KG, WOODAHL EL, et al. P450 pharmacogenetics in indigenous north American populations[J]. J Pers Med, 2018, 8(1): E9. DOI: 10.3390/jpm8010009.
    [19] 中国医师协会器官移植医师分会, 中华医学会器官移植学分会.中国肝癌肝移植临床实践指南(2018版)[J].临床肝胆病杂志, 2019, 35(2):275-280. DOI: 10.3969/j.issn.1001-5256.2019.02.008.

    Branch of Organ Transplant Physician of Chinese Medical Doctor Association, Branch of Organ Transplantation of Chinese Medical Association. The Chinese clinical practice guideline on liver transplantation for hepatocellular carcinoma (2018 edition)[J]. J Clin Hepatol, 2019, 35 (2):275-280. DOI: 10.3969/j.issn.1001-5256.2019.02.008.
    [20] MIN S, PAPAZ T, LAFRENIERE-ROULA M, et al. A randomized clinical trial of age and genotype-guided tacrolimus dosing after pediatric solid organ transplantation[J]. Pediatr Transplant, 2018, 22(7):e13285. DOI: 10.1111/petr.13285.
    [21] FANG Y, GAO J, WANG T, et al. Intraindividual variation and correlation of cytochrome P450 activities in human liver microsomes[J]. Mol Pharm, 2018, 15(11):5312-5318. DOI: 10.1021/acs.molpharmaceut.8b00787.
    [22] OU B, LIU Y, ZHANG T, et al. TLR9 rs352139 genetic variant promotes tacrolimus elimination in Chinese liver transplant patients during the early posttransplantation period[J]. Pharmacotherapy, 2019, 39(1):67-76. DOI: 10.1002/phar.2204.
    [23] SIBULESKY L, LI M, HANSEN RN, et al. Impact of cold ischemia time on outcomes of liver transplantation: a single center experience[J]. Ann Transplant, 2016, 21:145-151. doi: 10.12659/AOT.896190
    [24] 中华医学会器官移植学分会.器官移植免疫抑制剂临床应用技术规范(2019版)[J].器官移植, 2019, 10(3):213-226. DOI: 10.3969/j.issn.1674-7445.2019.03.001.

    Branch of Organ Transplantation of Chinese Medical Association. Technical specifcation for clinical application of immunosuppressive agents in organ transplantation (2019 edition)[J]. Organ Transplant, 2019, 10(3):213-226. DOI: 10.3969/j.issn.1674-7445.2019.03.001.
    [25] JI E, KIM MG, OH JM. CYP3A5 genotype-based model to predict tacrolimus dosage in the early postoperative period after living donor liver transplantation[J]. Ther Clin Risk Manag, 2018, 14:2119-2126. DOI: 10.2147/TCRM.S184376.
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出版历程
  • 收稿日期:  2020-04-22
  • 网络出版日期:  2021-01-19
  • 刊出日期:  2020-07-15

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