The purpose of this study was to investigate the potential impact of CYP3A4, CYP3A5, and CYP3A7 polymorphisms on the concentration and efficacy of tacrolimus in a cohort of pediatric patients with nephrotic range proteinuria.
Genetic variants including CYP3A5*3 (rs776746), CYP3A4*1G (rs2242480), rs4646437, and CYP3A7 rs2257401 and rs10211 were detected in 70 pediatric patients with nephrotic range proteinuria. The relationships of dose-adjusted trough concentration (C0) of tacrolimus with corresponding genotypes were investigated.
The tacrolimus concentration in patients without CYP3A5*3 A allele was 94% higher than those with A allele (90.7 vs 54.2, P = 0.00006). The CYP3A7 rs2257401 was also associated with the concentration of tacrolimus. The C allele carriers had an obviously lower C0 than the non-carriers (62.4 vs 90.7, P = 0.001). In addition, there were significant differences in tacrolimus concentration among CYP3A7 rs10211 G carriers and non-carriers; the latter had an almost twofold C0 of the former (101.8 vs 59.6, P = 0.0004).
Our study demonstrated the associations between CYP3A5*3, CYP3A7 rs2257401 and rs10211, and tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Children with CYP3A5*3 A, CYP3A7 rs2257401 C, and rs10211 G alleles might need a higher dose of tacrolimus.
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Tang JT, Andrews LM, van Gelder T, Shi YY, van Schaik RH, Wang LL, Hesselink DA (2016) Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations. Expert Opin Drug Metab Toxicol 12(5):555–565. https://doi.org/10.1517/17425255.2016.1170808
Sun JY, Xu ZJ, Sun F, Guo HL, Ding XS, Chen F, Xu J (2018) Individualized tacrolimus therapy for pediatric nephrotic syndrome: considerations for ontogeny and pharmacogenetics of CYP3A. Curr Pharm Des 24:2765–2773. https://doi.org/10.2174/1381612824666180829101836
Li S, Yang H, Guo P, Ao X, Wan J, Li Q, Tan L (2017) Efficacy and safety of immunosuppressive medications for steroid-resistant nephrotic syndrome in children: a systematic review and network meta-analysis. Oncotarget 8(42):73050–73062. https://doi.org/10.18632/oncotarget.20377
Jahan A, Prabha R, Chaturvedi S, Mathew B, Fleming D, Agarwal I (2015) Clinical efficacy and pharmacokinetics of tacrolimus in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 30(11):1961–1967. https://doi.org/10.1007/s00467-015-3133-3
Yang EM, Lee ST, Choi HJ, Cho HY, Lee JH, Kang HG, Park YS, Cheong HI, Ha IS (2016) Tacrolimus for children with refractory nephrotic syndrome: a one-year prospective, multicenter, and open-label study of Tacrobell(R), a generic formula. World J Pediatr 12(1):60–65. https://doi.org/10.1007/s12519-015-0062-y
Pulk RA, Schladt DS, Oetting WS, Guan W, Israni AK, Matas AJ, Remmel RP, Jacobson PA, De KAFI (2015) Multigene predictors of tacrolimus exposure in kidney transplant recipients. Pharmacogenomics 16(8):841–854. https://doi.org/10.2217/pgs.15.42
Prytula A, van Gelder T (2019) Clinical aspects of tacrolimus use in paediatric renal transplant recipients. Pediatr Nephrol 34(1):31–43. https://doi.org/10.1007/s00467-018-3892-8
Johnson TN (2003) The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children. Toxicology 192(1):37–48
Stevens JC, Hines RN, Gu C, Koukouritaki SB, Manro JR, Tandler PJ, Zaya MJ (2003) Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther 307(2):573–582. https://doi.org/10.1124/jpet.103.054841
Blake MJ, Castro L, Leeder JS, Kearns GL (2005) Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med 10(2):123–138. https://doi.org/10.1016/j.siny.2004.11.001
Madsen MJ, Bergmann TK, Brosen K, Thiesson HC (2017) The pharmacogenetics of tacrolimus in corticosteroid-sparse pediatric and adult kidney transplant recipients. Drugs R&D 17(2):279–286. https://doi.org/10.1007/s40268-017-0177-9
Yang M, Wang M, Gui H, Mao C (2018) Influence of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics/pharmacodynamics of tacrolimus in pediatric patients. Curr Drug Metab 19:1141–1151. https://doi.org/10.2174/1389200219666180925090228
Yang HY, Lee QP, Rettie AE, Juchau MR (1994) Functional cytochrome P4503A isoforms in human embryonic tissues: expression during organogenesis. Mol Pharmacol 46(5):922–928
Schuetz JD, Beach DL, Guzelian PS (1994) Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics 4(1):11–20
Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T (1997) Expression of CYP3A in the human liver--evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 247(2):625–634
Sun B, Guo Y, Gao J, Shi W, Fan G, Li X, Qiu J, Qin Y, Liu G (2017) Influence of CYP3A and ABCB1 polymorphisms on cyclosporine concentrations in renal transplant recipients. Pharmacogenomics 18(16):1503–1513. https://doi.org/10.2217/pgs-2017-0127
Zhang JJ, Zhang H, Ding XL, Ma S, Miao LY (2013) Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers. Eur J Clin Pharmacol 69(4):807–812. https://doi.org/10.1007/s00228-012-1432-1
Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27(4):383–391. https://doi.org/10.1038/86882
Fukushima-Uesaka H, Saito Y, Watanabe H, Shiseki K, Saeki M, Nakamura T, Kurose K, Sai K, Komamura K, Ueno K, Kamakura S, Kitakaze M, Hanai S, Nakajima T, Matsumoto K, Saito H, Goto Y, Kimura H, Katoh M, Sugai K, Minami N, Shirao K, Tamura T, Yamamoto N, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J (2004) Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population. Hum Mutat 23(1):100. https://doi.org/10.1002/humu.9210
Diekstra MH, Belaustegui A, Swen JJ, Boven E, Castellano D, Gelderblom H, Mathijssen RH, Garcia-Donas J, Rodriguez-Antona C, Rini BI, Guchelaar HJ (2017) Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma. Pharmacogenomics J 17(1):42–46. https://doi.org/10.1038/tpj.2015.100
Chau CH, Price DK, Till C, Goodman PJ, Chen X, Leach RJ, Johnson-Pais TL, Hsing AW, Hoque A, Tangen CM, Chu L, Parnes HL, Schenk JM, Reichardt JK, Thompson IM, Figg WD (2015) Finasteride concentrations and prostate cancer risk: results from the Prostate Cancer Prevention Trial. PLoS One 10(5):e0126672. https://doi.org/10.1371/journal.pone.0126672
He HR, Sun JY, Ren XD, Wang TT, Zhai YJ, Chen SY, Dong YL, Lu J (2015) Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole. Eur J Clin Microbiol Infect Dis 34(4):811–819. https://doi.org/10.1007/s10096-014-2294-5
Li CJ, Li L, Lin L, Jiang HX, Zhong ZY, Li WM, Zhang YJ, Zheng P, Tan XH, Zhou L (2014) Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. PLoS One 9(1):e86206. https://doi.org/10.1371/journal.pone.0086206
Sohn M, Kim MG, Han N, Kim IW, Gim J, Min SI, Song EY, Kim YS, Jung HS, Shin YK, Ha J, Oh JM (2018) Whole exome sequencing for the identification of CYP3A7 variants associated with tacrolimus concentrations in kidney transplant patients. Sci Rep 8(1):18064. https://doi.org/10.1038/s41598-018-36085-w
Burk O, Tegude H, Koch I, Hustert E, Wolbold R, Glaeser H, Klein K, Fromm MF, Nuessler AK, Neuhaus P, Zanger UM, Eichelbaum M, Wojnowski L (2002) Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine. J Biol Chem 277(27):24280–24288. https://doi.org/10.1074/jbc.M202345200
Sim SC, Edwards RJ, Boobis AR, Ingelman-Sundberg M (2005) CYP3A7 protein expression is high in a fraction of adult human livers and partially associated with the CYP3A7*1C allele. Pharmacogenet Genomics 15(9):625–631
Knox B, Wang Y, Rogers LJ, Xuan J, Yu D, Guan H, Chen J, Shi T, Ning B, Kadlubar SA (2018) A functional SNP in the 3′-UTR of TAP2 gene interacts with microRNA hsa-miR-1270 to suppress the gene expression. Environ Mol Mutagen 59(2):134–143. https://doi.org/10.1002/em.22159
Wei R, Yang F, Urban TJ, Li L, Chalasani N, Flockhart DA, Liu W (2012) Impact of the interaction between 3′-UTR SNPs and microRNA on the expression of human xenobiotic metabolism enzyme and transporter genes. Front Genet 3:248. https://doi.org/10.3389/fgene.2012.00248
Roy J, Mallick B (2017) Altered gene expression in late-onset Alzheimer’s disease due to SNPs within 3′UTR microRNA response elements. Genomics 109(3–4):177–185. https://doi.org/10.1016/j.ygeno.2017.02.006
Zong YP, Wang ZJ, Zhou WL, Zhou WM, Ma TL, Huang ZK, Zhao CC, Xu Z, Tan RY, Gu M (2017) Effects of CYP3A5 polymorphisms on tacrolimus pharmacokinetics in pediatric kidney transplantation: a systematic review and meta-analysis of observational studies. World J Pediatr 13(5):421–426. https://doi.org/10.1007/s12519-017-0035-4
Asempa TE, Rebellato LM, Hudson S, Briley K, Maldonado AQ (2018) Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients. Clin Transpl 32(1). https://doi.org/10.1111/ctr.13162
Qu L, Lu Y, Ying M, Li B, Weng C, Xie Z, Liang L, Lin C, Yang X, Feng S, Wang Y, Shen X, Zhou Q, Chen Y, Chen Z, Wu J, Lin W, Shen Y, Qin J, Xu H, Xu F, Wang J, Chen J, Jiang H, Huang H (2017) Tacrolimus dose requirement based on the CYP3A5 genotype in renal transplant patients. Oncotarget 8(46):81285–81294. https://doi.org/10.18632/oncotarget.18150
Rojas L, Neumann I, Herrero MJ, Boso V, Reig J, Poveda JL, Megias J, Bea S, Alino SF (2015) Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J 15(1):38–48. https://doi.org/10.1038/tpj.2014.38
Buendia JA, Bramuglia G, Staatz CE (2014) Effects of combinational CYP3A5 6986A>G polymorphism in graft liver and native intestine on the pharmacokinetics of tacrolimus in liver transplant patients: a meta-analysis. Ther Drug Monit 36(4):442–447. https://doi.org/10.1097/FTD.0000000000000032
Lunde I, Bremer S, Midtvedt K, Mohebi B, Dahl M, Bergan S, Asberg A, Christensen H (2014) The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur J Clin Pharmacol 70(6):685–693. https://doi.org/10.1007/s00228-014-1656-3
Zuo XC, Ng CM, Barrett JS, Luo AJ, Zhang BK, Deng CH, Xi LY, Cheng K, Ming YZ, Yang GP, Pei Q, Zhu LJ, Yuan H, Liao HQ, Ding JJ, Wu D, Zhou YN, Jing NN, Huang ZJ (2013) Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis. Pharmacogenet Genomics 23(5):251–261. https://doi.org/10.1097/FPC.0b013e32835fcbb6
Wang X, Yang Y, Liu Z, Xiao C, Gao L, Zhang W, Zhang W, Wang Z (2019) Switching immunosuppression from cyclosporine to tacrolimus in kidney transplant recipients based on CYP3A5 genotyping. Ther Drug Monit 41(1):97–101. https://doi.org/10.1097/FTD.0000000000000579
Hongxia Liu had financial support from the Shanghai Municipal Commission of Health and Family Planning (No. 20164Y0122). Dr. Xiaoyan Qiu had support from the Shanghai “Rising Stars of Medical Talent” Youth Development Program-Clinical Pharmacist Program, National Natural Science Foundation of China (No. 81302854), and Natural Science Foundation of Shanghai (No. 13ZR1405200).
The study was performed in accordance with the Declaration of Helsinki and its amendments. Protocols were approved by the Ethics Committee of Shanghai Children’s Hospital and written informed consents were obtained from all subjects.
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Liu, H., Xu, Q., Huang, W. et al. CYP3A5 and CYP3A7 genetic polymorphisms affect tacrolimus concentration in pediatric patients with nephrotic range proteinuria. Eur J Clin Pharmacol 75, 1533–1540 (2019). https://doi.org/10.1007/s00228-019-02726-w
- Pediatric patients
- Nephrotic range proteinuria