Influence of Genetic Polymorphisms in CYP3A5, CYP3A4, and MDR1 on Tacrolimus Metabolism after kidney transplantation

Mirgul Bayanova 1, Aida Zhenissova 2 * , Lyazzat Nazarova 1, Aizhan Abdikadirova 1, Malika Sapargalieyva 1, Dias Malik 1, Aidos Bolatov 3, Saitkarim Abdugafarov 4, Mels Assykbayev 5, Sholpan Altynova 6, Yuriy Pya 7
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1 Department of Clinical and Genetic Diagnostics, CAD of Laboratory Medicine, Pathology and Genetics, “University Medical Center” CF, Astana, Kazakhstan
2 “Medical genetics” Residency program, Department of Clinical and Genetic Diagnostics, CAD of Laboratory Medicine, Pathology and Genetics, “University Medical Center” CF, Astana, Kazakhstan
3 Shenzhen University Medical School, Shenzhen University, Shenzhen, China
4 Center for Hepatopancreatobiliary Surgery, Hematology and Organ Transplantation, “National Research Oncology Center”, Astana, Kazakhstan
5 Organ Transplantation Sector, Center for Hepatopancreatobiliary Surgery, Hematology and Organ Transplantation, “National Research Oncology Center”, Astana, Kazakhstan
6 Deputy Medical Director, “University Medical Center” CF, Astana, Kazakhstan
7 Chairman of the board, “University Medical Center” CF, Astana, Kazakhstan
* Corresponding Author
J CLIN MED KAZ, Volume 21, Issue 2, pp. 11-17.
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Author Contributions: Conceptualization, M.B. and A.B.; methodology, M.B., L.K. and A.B.; formal analysis, L.K., A.A., M.S., S.Ab. and M.A.; investigation, L.K., A.A., M.S., S.Ab. and M.A.; resources, A.Z., D.M. and A.B.; data curation, A.A., M.S., S.Ab. and M.A.; writing – original draft preparation, A.Z. and D.M.; writing – review and editing, M.B., A.B. and S.Al.; visualization, A.Z. and D.M.; supervision, M.B. and L.K.; project administration, M.B. and S.Al.; funding acquisition, Y.P.. All authors have read and agreed to the published version of the manuscript.


Kidney transplantation stands as the ultimate recourse for restoring vital organ functions, particularly in cases of end-stage kidney disease where alternative treatments, such as dialysis, prove less effective. With over 102,000 kidney transplants conducted globally in 2022, the demand for organ transplantation is ever-increasing, fueled by a rising incidence of end-stage renal disease attributed to causes like diabetes and hypertension.
Despite significant advancements in kidney transplantation, immunosuppressive therapy remains crucial to preventing graft rejection. Tacrolimus (TAC), a calcineurin inhibitor, plays a pivotal role in this regard. Discovered in 1984, TAC inhibits T-lymphocyte activation, preventing acute rejection by disrupting the transcription of crucial genes involved in early T-cell activation. However, the use of TAC is not without challenges. The drug exhibits serious side effects, a narrow therapeutic index, and unpredictable pharmacokinetics. Therapeutic drug monitoring (TDM) becomes imperative in daily practice to maintain TAC blood concentrations within the therapeutic range. This literature review delves into the genetic aspects influencing TAC metabolism, focusing on key polymorphisms in CYP3A5, CYP3A4, and ABCB1 genes. Genetic variations in CYP3A5, a major enzyme in TAC metabolism, impact enzyme activity, necessitating personalized dosing strategies. CYP3A4 polymorphisms, especially CYP3A4*22, demonstrate associations with altered TAC clearance and dose requirements. The ABCB1 gene, encoding P-glycoprotein, another player in TAC pharmacokinetics, also exhibits polymorphisms influencing drug absorption and distribution. The ABCB1 3435C>T variant, in particular, shows potential implications on Tacrolimus bioavailability. Understanding these genetic variations aids in the development of personalized dosing regimens. Studies suggest that tailoring TAC doses based on CYP3A5 genotypes significantly improves the proportion of patients achieving therapeutic concentrations. Additionally, incorporating genetic information, particularly CYP3A4*22, into dosing strategies enhances the precision of TAC therapy, reducing the risk of adverse effects.


Bayanova M, Zhenissova A, Nazarova L, Abdikadirova A, Sapargalieyva M, Malik D, et al. Influence of Genetic Polymorphisms in CYP3A5, CYP3A4, and MDR1 on Tacrolimus Metabolism after kidney transplantation. J CLIN MED KAZ. 2024;21(2):11-7.


  • Chandraker, Anil, Melissa Y. Yeung, and Christophe Legendre. "Kidney transplantation in adults: Overview of care of the adult kidney transplant recipient." UpToDate. com (2018).
  • Hatzinger M, Stastny M, Grützmacher P, Sohn M. Die Geschichte der Nierentransplantation [The history of kidney transplantation]. Der Urologe. Ausg. A. 2016;55(10):1353–1359.
  • Total global kidney transplants by region 2022. (2023, November 20). Statista.
  • Abramyan S, Hanlon M. Kidney Transplantation. [Updated 2023 Jan 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
  • Tacrolimus: Uses, Interactions, Mechanism of Action | DrugBank Online. (n.d.). DrugBank.,formation%20of%20a%20fused%20ring
  • Mendrinou E, Mashaly ME, Al Okily AM, Mohamed ME, Refaie AF, Elsawy EM, Saleh HH, Sheashaa H, Patrinos GP. CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients. Frontiers in pharmacology. 2020;11:1218.
  • Cheng F, Li Q, Wang J, Hu M, Zeng F, Wang Z, Zhang Y. Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients. Pharmacogenomics and personalized medicine. 2021;14: 1463–1474.
  • Lee SJ, Usmani KA, Chanas B, Ghanayem B, Xi T, Hodgson E, Mohrenweiser HW, Goldstein JA. Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups. Pharmacogenetics. 2003;13(8):461–472.
  • Lamba J, Hebert JM, Schuetz EG, Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenetics and genomics. 2012;22(7):555–558.
  • Albekairy A, Alkatheri A, Fujita S, Hemming A, Howard R, Reed A, Karlix J. Cytochrome P450 3A4FNx011B as pharmacogenomic predictor of tacrolimus pharmacokinetics and clinical outcome in the liver transplant recipients. Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association. 2013;19(2): 89–95.
  • Duricová J, Grundmann M. Cytochróm P450 3A polymorfizmus a jeho význam pri terapii cyklosporínom a takrolimom u transplantovaných pacientov [Cytochrome P450 3A polymorphism and its importance in cyclosporine and tacrolimus therapy in transplanted patients]. Ceska Slov Farm. 2007;56(5):220-224.
  • Quteineh L, Verstuyft C, Furlan V, et al. Influence of CYP3A5 genetic polymorphism on tacrolimus daily dose requirements and acute rejection in renal graft recipients. Basic Clin Pharmacol Toxicol. 2008;103(6):546-552.
  • 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.
  • Thompson EE, Kuttab-Boulos H, Witonsky D, Yang L, Roe BA, Di Rienzo A. CYP3A variation and the evolution of salt-sensitivity variants. Am J Hum Genet. 2004;75(6):1059-1069.
  • Chen L, Prasad GVR. CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment. Pharmgenomics Pers Med. 2018;11:23-33.
  • Baimakhanov BB, Chormanov AT, Medeubekov US, Syrymov ZM, Madadov IK, Dabyltaeva KS, Belgibaev EB, Nabiev ES, Saduakas NT, Baiyz AZ, Aipov BR. Genetic polymorphisms of CYP3A5 as a key regulator of pharmacokinetics of tacrolimus in kidney transplant patients: evidence in kazakh population. Vestnik hirurgii Kazahstana. 2021; 1(66):5-9.
  • Elens L, van Gelder T, Hesselink DA, Haufroid V, van Schaik RH. CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics. 2013;14(1):47-62.
  • Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 2011;11(4):274-286.
  • Yang M, Huan G, Wang M. Influence of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics/Pharmacodynamics of Tacrolimus in Pediatric Patients. Curr Drug Metab. 2018;19(14):1141-1151.
  • Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97:3473–8.
  • Terrazzino S, Quaglia M, Stratta P, Canonico PL, Genazzani AA. The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: a systematic review and meta-analysis. Pharmacogenet Genomics. 2012;22(8):642-645.
  • Rojas L, Neumann I, Herrero MJ, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 2015;15(1):38-48.
  • Chen P, Li J, Li J, et al. Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients. J Clin Pharm Ther. 2017;42(1):93-97.
  • Thervet E, Loriot MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. 2010;87(6):721-726.
  • Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015;98(1):19-24.
  • Tavira B, Coto E, Diaz-Corte C, Alvarez V, López-Larrea C, Ortega F. A search for new CYP3A4 variants as determinants of tacrolimus dose requirements in renal-transplanted patients. Pharmacogenet Genomics. 2013;23(8):445-448.
  • Kuypers DR, de Loor H, Naesens M, Coopmans T, de Jonge H. Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients. Pharmacogenet Genomics. 2014;24(12):597-606.
  • Lunde I, Bremer S, Midtvedt K, et al. The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur J Clin Pharmacol. 2014;70(6):685-693.
  • De Jonge H, Elens L, de Loor H, van Schaik RH, Kuypers DR. The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients. Pharmacogenomics J. 2015;15(2):144-152.
  • Lloberas N, Elens L, Llaudó I, et al. The combination of CYP3A4*22 and CYP3A5*3 single-nucleotide polymorphisms determines tacrolimus dose requirement after kidney transplantation. Pharmacogenet Genomics. 2017;27(9):313-322.
  • Madsen MJ, Bergmann TK, Brøsen K, Thiesson HC. The Pharmacogenetics of Tacrolimus in Corticosteroid-Sparse Pediatric and Adult Kidney Transplant Recipients. Drugs R D. 2017;17(2):279-286.
  • Vanhove T, Hasan M, Annaert P, Oswald S, Kuypers DRJ. Pretransplant 4β-hydroxycholesterol does not predict tacrolimus exposure or dose requirements during the first days after kidney transplantation. Br J Clin Pharmacol. 2017;83(11):2406-2415.
  • Scheibner A, Remmel R, Schladt D, et al. Tacrolimus Elimination in Four Patients With a CYP3A5*3/*3 CYP3A4*22/*22 Genotype Combination. Pharmacotherapy. 2018;38(7):e46-e52.
  • Kim JS, Shim S, Yee J, Choi KH, Gwak HS. Effects of CYP3A4*22 polymorphism on trough concentration of tacrolimus in kidney transplantation: a systematic review and meta-analysis. Front Pharmacol. 2023;14:1201083.
  • Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634.
  • Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-W64.
  • Peng W, Lin Y, Zhang H, Meng K. Effect of ABCB1 3435C>T Genetic Polymorphism on Pharmacokinetic Variables of Tacrolimus in Adult Renal Transplant Recipients: A Systematic Review and Meta-analysis. Clin Ther. 2020;42(10):2049-2065.
  • Vannaprasaht S, Limwattananon C, Anutrakulchai S, Chan-On C. Effect of CYP3A5 genotype on hospitalization cost for kidney transplantation. Int J Clin Pharm. 2019;41(1):88-95.
  • Provenzani A, Santeusanio A, Mathis E, et al. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol. 2013;19(48):9156-9173.
  • Kitzmiller JP, Groen DK, Phelps MA, Sadee W. Pharmacogenomic testing: relevance in medical practice: why drugs work in some patients but not in others. Cleve Clin J Med. 2011;78(4):243-257.
  • Fleeman N, McLeod C, Bagust A, et al. The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation. Health Technol Assess. 2010;14(3):1-iii.
  • Berm EJ, Looff Md, Wilffert B, et al. Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature. PLoS One. 2016;11(1):e0146262.