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Polymorphisms in the CYP3A5 gene significantly affect the pharmacokinetics of sirolimus after kidney transplantation

    Jiawen Liu‡

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Dengyuan Feng‡

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Xuechun Kan‡

    Department of Anatomy, Nanjing Medical University, Nanjing, 211166, PR China

    ,
    Ming Zheng

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Xiang Zhang

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Zijie Wang

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Li Sun

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Hao Chen

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Xiang Gao

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Ting Lu

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Min Gu

    *Author for correspondence: Tel.: +86 025 6830 3181;

    E-mail Address: lancetgu@aliyun.com

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    ,
    Ruoyun Tan

    **Author for correspondence: Tel.: +86 025 6830 3181;

    E-mail Address: tanruoyun112@vip.sina.com

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    &
    Zhijian Han

    ***Author for correspondence: Tel.: +86 025 6830 3181;

    E-mail Address: fishermanhzj@126.com

    Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China

    Published Online:https://doi.org/10.2217/pgs-2021-0083

    Aim: Sirolimus (SIR) is an immunosuppressant with limitations, including a narrow treatment window, multiple adverse reactions and large differences within and among individuals. Objective: The correlation between numerous SNPs and SIR in terms of trough concentration in the early stage after kidney transplantation was analyzed. Materials & methods: A retrospective cohort study involving 69 kidney transplantation recipients was designed. Blood samples were collected to extract total DNAs, and trough SIR concentrations were measured. Logistic regression was used to analyze the association between SNPs and SIR trough concentrations. Results: At 7 days, 1 month and 3 months, the mean SIR trough concentration of patients in the CYP3A5 rs4646453-CC group was significantly higher than that in the CYP3A5 rs4646453-AA and CYP3A5 rs4646453-CA groups (p < 0.001) and CYP3A5 rs15524-AA group was significantly higher than that in the CYP3A5 rs15524-AG and CYP3A5 rs15524-GG groups (p < 0.001). Conclusion: Our study indicated that both CYP3A5 rs4646453 and CYP3A5 rs15524 had a certain influence on SIR trough concentration at 7 days, 1 month and 3 months.

    References

    • 1. Ojo AO, Hanson JA, Meier-Kriesche H et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J. Am. Soc. Nephrol. 12(3), 589–597 (2001).
    • 2. Laupacis A, Keown P, Pus N et al. A study of the quality of life and cost-utility of renal transplantation. Kidney Int. 50(1), 235–242 (1996).
    • 3. Browne BJ, Kahan BD. Renal transplantation. Surg. Clin. N. Am. 74(5), 1097–1116 (1994).
    • 4. Jain D, Haddad DB, Goel N. Choice of dialysis modality prior to kidney transplantation: does it matter? World J. Nephrol. 8(1), 1–10 (2019).
    • 5. Lebranchu Y, Baan C, Biancone L et al. Pretransplant identification of acute rejection risk following kidney transplantation. Transpl. Int. 27(2), 129–138 (2014).
    • 6. Davis S, Cooper JE. Acute antibody-mediated rejection in kidney transplant recipients. Transplant. Rev. 31(1), 47–54 (2017).
    • 7. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am. J. Transplant. 9(Suppl. 3), S1–S155 (2009).
    • 8. Moes DJ, Guchelaar HJ, de Fijter JW. Sirolimus and everolimus in kidney transplantation. Drug Discov. Today 20(10), 1243–1249 (2015).
    • 9. Morath C, Arns W, Schwenger V et al. Sirolimus in renal transplantation. Nephrol. Dial. Transplant. 22(Suppl. 8), viii61–viii65 (2007).
    • 10. Halleck F, Duerr M, Waiser J et al. An evaluation of sirolimus in renal transplantation. Expert Opin. Drug Metab. Toxicol. 8(10), 1337–1356 (2012).
    • 11. Shuang F, Zijie W, Hao C et al. Quadruple low-dose immunosuppressant maintenance therapy protocol in renal transplanted recipients within three months after renal transplantation. Chinese J. Organ Transplant. 41(03), 174–179 (2020).
    • 12. Kirchner GI, Winkler M, Mueller L et al. Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the first dose of SDZ RAD. Br. J. Clin. Pharmacol. 50(5), 449–454 (2000).
    • 13. Li Y, Yan L, Shi Y, Bai Y, Tang J, Wang L. CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients. Springer Plus 4, 637 (2015).
    • 14. Tamashiro EY, Felipe CR, Genvigir FDV et al. Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients. Drug Metab. Pers. Ther. 32(2), 89–95 (2017).
    • 15. Santoro A, Felipe CR, Tedesco-Silva H et al. Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients. Pharmacogenomics 12(9), 1293–1303 (2011).
    • 16. Achour B, Barber J, Rostami-Hodjegan A. Expression of hepatic drug-metabolizing cytochrome P450 enzymes and their intercorrelations: a meta-analysis. Drug Metab. Dispos. 42(8), 1349–1356 (2014).
    • 17. Lolita L, Zheng M, Zhang X et al. The genetic polymorphism of CYP3A4 rs2242480 is associated with sirolimus trough concentrations among adult renal transplant recipients. Curr. Drug Metab. 21, 1–10 (2020).
    • 18. Le Meur Y, Djebli N, Szelag JC et al. CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients. Clin. Pharmacol. Ther. 80(1), 51–60 (2006).
    • 19. Żochowska D, Wyzgał J, Pączek L. Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients. Ann. Transplant. 17(3), 36–44 (2012).
    • 20. Jones-Hughes T, Snowsill T, Haasova M et al. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model. Health Technol Assess. 20(62), 1–594 (2016).
    • 21. Cibulskis K, Lawrence MS, Carter SL et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nature Biotechnol. 31(3), 213–219 (2013).
    • 22. Gabriel SB, Schaffner SF, Nguyen H et al. The structure of haplotype blocks in the human genome. Science 296(5576), 2225–2229 (2002).
    • 23. Lim MA, Kohli J, Bloom RD. Immunosuppression for kidney transplantation: where are we now and where are we going? Transplant Rev. (Orlando) 31(1), 10–17 (2017).
    • 24. Lolodi O, Wang YM, Wright WC, Chen T. Differential regulation of CYP3A4 and CYP3A5 and its implication in drug discovery. Curr. Drug Metab. 18(12), 1095–1105 (2017).
    • 25. Miao LY, Huang CR, Hou JQ, Qian MY. Association study of ABCB1 and CYP3A5 gene polymorphisms with sirolimus trough concentration and dose requirements in Chinese renal transplant recipients. Biopharm. Drug Dispos. 29(1), 1–5 (2008).
    • 26. Nair SS, Sarasamma S, Gracious N, George J, Anish TS, Radhakrishnan R. Polymorphism of the CYP3A5 gene and its effect on tacrolimus blood level. Exp. Clin. Transplant. 13(Suppl. 1), 197–200 (2015).
    • 27. Luo X, Zhu LJ, Cai NF, Zheng LY, Cheng ZN. Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5(*)3 genotype in Chinese renal transplant recipients. Acta Pharmacologica Sinica 37(4), 555–560 (2016).
    • 28. Vannaprasaht S, Limwattananon C, Anutrakulchai S, Chan-On C. Effect of CYP3A5 genotype on hospitalization cost for kidney transplantation. Int. J. Clin. Pharm. 41(1), 88–95 (2019).
    • 29. Wang HF, Qiu F, Wu X et al. Steady-state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients. Clin. Pharmacol. Drug Dev. 3(3), 235–241 (2014).
    • 30. Djebli N, Rousseau A, Hoizey G et al. Sirolimus population pharmacokinetic/pharmacogenetic analysis and bayesian modelling in kidney transplant recipients. Clin. Pharmacokinet. 45(11), 1135–1148 (2006).