Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Combined Role of CYP3A4 and CYP3A5 genetic variants in tacrolimus dose-adjusted trough levels: a clinical retrospective study in kidney transplant patients

The Pharmacogenomics Journal volume 26, Article number: 1 (2026) Cite this article

Subjects

Abstract

Tacrolimus, a calcineurin inhibitor with a narrow therapeutic index, requires precise dosing to optimize efficacy and minimize adverse effects in kidney transplant recipients. Although CYP3A5 genetic variants influence tacrolimus pharmacokinetics, they do not fully explain inter-individual differences. This retrospective study evaluated the combined impact of CYP3A4 [*1B (rs2740574), *1 G (rs2242480), *22 (rs35599367)] and CYP3A5 [*3 (rs776746), *6 (rs10264272), *7 (rs41303343)] genetic variants, as CYP3A phenotypes, on tacrolimus dose-adjusted trough concentrations (C0/D), in 94 Greek kidney transplant recipients at five time points during the first-year post-transplantation. Significant differences in tacrolimus C0/D ratios were observed across the groups. Group 4 (CYP3A5 expressers, carriers of CYP3A4*1B or *1 G) had consistently lower C0/D ratios compared to Groups 1 and 2 (CYP3A5 nonexpressers, carriers of CYP3A4*22 or CYP3A4 *1/*1) at multiple timepoints (p ≤ 0.022 and p ≤ 0.004, respectively). These findings suggest that CYP3A phenotypes could improve tacrolimus dosing decisions in kidney transplant recipients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Tacrolimus daily doses across CYP3A phenotype groups over the first-year post-transplantation.
Fig. 2: Tacrolimus C0/D ratios across CYP3A phenotype groups over the first-year post-transplantation.
Fig. 3: Tacrolimus C0/D ratios in CYP3A4 Expresser groups over the first-year post-transplantation.
Fig. 4: Tacrolimus C0/D ratios in CYP3A5 Expressers and Non-Expressers over the first-year post-transplantation.

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Brunet M, van Gelder T, Åsberg A, Haufroid V, Hesselink DA, Langman L, et al. Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit. 2019;41:261–307.

    Article  CAS  PubMed  Google Scholar 

  2. Shuker N, van Gelder T, Hesselink DA. Intra-patient variability in tacrolimus exposure: Causes, consequences for clinical management. Transplant Rev. 2015;29:78–84.

    Article  Google Scholar 

  3. Zhang X, Lin G, Tan L, Li J. Current progress of tacrolimus dosing in solid organ transplant recipients: Pharmacogenetic considerations. Biomedicine & Pharmacotherapy. 2018;102:107–14.

    Article  CAS  Google Scholar 

  4. Passey C, Birnbaum AK, Brundage RC, Oetting WS, Israni AK, Jacobson PA. Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol. 2011;72:948–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Picard N, Bergan S, Marquet P, van Gelder T, Wallemacq P, Hesselink DA, et al. Pharmacogenetic Biomarkers Predictive of the Pharmacokinetics and Pharmacodynamics of Immunosuppressive Drugs. Ther Drug Monit. 2016;38:S57–69.

    Article  PubMed  Google Scholar 

  6. Brunet M, Pastor-Anglada M. Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics. Pharmaceutics. 2022;14:1755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Eddour DC, 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;14:147–54.

    Article  CAS  PubMed  Google Scholar 

  8. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–91.

    Article  CAS  PubMed  Google Scholar 

  9. Birdwell K, Decker B, Barbarino J, Peterson J, Stein C, Sadee W, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015;98:19–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu M, Hernandez S, Aquilante CL, Deininger KM, Lindenfeld J, Schlendorf KH, et al. Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influence on tacrolimus dose adjusted concentrations in adult heart transplant recipients. Pharmacogenomics J. 2024;24:4.

    Article  PubMed  Google Scholar 

  11. 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;11:274–86.

    Article  PubMed  Google Scholar 

  12. Shi WL, Tang HL, Zhai SD. Effects of the CYP3A4*1B Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis. PLoS One. 2015;10:e0127995.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Furuse M, Hosomi S, Nishida Y, Itani S, Nadatani Y, Fukunaga S, et al. The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients. PLoS One. 2021;16:e0250597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zuo, Ng Xcong, Barrett CM, Luo JS, jing A, Zhang Bkui, et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients. Pharmacogenet Genomics. 2013;23:251–61.

    Article  CAS  PubMed  Google Scholar 

  15. Mendrinou E, Mashaly ME, Al Okily AM, Mohamed ME, Refaie AF, Elsawy EM, et al. CYP3A5 Gene-Guided Tacrolimus Treatment of Living-Donor Egyptian Kidney Transplanted Patients. Front Pharmacol. 2020;11:1–7.

    Article  Google Scholar 

  16. Brazeau DA, Attwood K, Meaney CJ, Wilding GE, Consiglio JD, Chang SS, et al. Beyond Single Nucleotide Polymorphisms: CYP3A5∗3∗6∗7 Composite and ABCB1 Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients. Front Genet. 2020;11:11.

    Article  Google Scholar 

  17. Machiela MJ, Chanock SJ. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31:3555–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oetting WS, Schladt DP, Guan W, Miller MB, Remmel RP, Dorr C, et al. Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles. American Journal of Transplantation. 2016;16:574–82.

    Article  CAS  PubMed  Google Scholar 

  19. Suarez-Kurtz G, Struchiner CJ. Pharmacogenomic implications of the differential distribution of CYP3A5 metabolic phenotypes among Latin American populations. Pharmacogenomics. 2024;25:187–95.

    Article  CAS  PubMed  Google Scholar 

  20. Pallet N, Jannot AS, El Bahri M, Etienne I, Buchler M, de Ligny BH, et al. Kidney Transplant Recipients Carrying the CYP3A4*22 Allelic Variant Have Reduced Tacrolimus Clearance and Often Reach Supratherapeutic Tacrolimus Concentrations. American Journal of Transplantation. 2015;15:800–5.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

  22. Liu M, Shaver CM, Birdwell KA, Heeney SA, Shaffer CM, Van Driest SL. Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients. Pharmacogenet Genomics. 2022;32:209–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Concha J, Sangüesa E, Ribate MP, García CB. CYP3A4*1B but Not CYP3A5*3 as Determinant of Long-Term Tacrolimus Dose Requirements in Spanish Solid Organ Transplant Patients. Int J Mol Sci. 2024;25:11327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tsironi A, Lazaros K, Mendrinou E, Papasotiriou M, Siamoglou S, Kydonopoulou K, et al. Impact of CYP3A4 and ABCB1 genetic variants on tacrolimus dosing in Greek kidney transplant recipients. Front Pharmacol. 2025;16.

  25. Aouam K, Kolsi A, Kerkeni E, Ben Fredj N, Chaabane A, Monastiri K, et al. Influence of Combined CYP3A4 and CYP3A5 Single-Nucleotide Polymorphisms on Tacrolimus Exposure in Kidney Transplant Recipients: A Study According to the Post-Transplant Phase. Pharmacogenomics. 2015;16:2045–54.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all the patients who consented to be involved in the study.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Laboratory of Pharmacogenomics and Individualized Therapy, University of Patras School of Health Sciences, Patras, Greece

    Anna Tsironi, Stavroula Siamoglou & George P. Patrinos

  2. Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research ‘Demokritos’, Athens, Greece

    Effrosyni Mendrinou

  3. ANALYSI S.A., Thessaloniki, Greece

    Kyriaki Kydonopoulou, Alexandra Gerou & Spyridon Gerou

  4. College of Medicine and Health Sciences, Department of Genetics and Genomics, United Arab Emirates University, Al-Ain, Abu Dhabi, UAE

    Anne John, Bassam R. Ali & George P. Patrinos

  5. Department of Nephrology and Kidney Transplantation, University Hospital of Patras, Patras, Greece

    Marios Papasotiriou

  6. Zayed Center for Health Sciences, United Arab Emirates University, Al-Ain, Abu Dhabi, UAE

    George P. Patrinos

  7. Faculty of Medicine and Health Sciences, Department of Pathology, Clinical Bioinformatics Unit, Erasmus University Medical Center, Rotterdam, the Netherlands

    George P. Patrinos

  8. Hellenic Pasteur Institute, Athens, Greece

    George P. Patrinos

Authors
  1. Anna Tsironi
    View author publications

    Search author on:PubMed Google Scholar

  2. Effrosyni Mendrinou
    View author publications

    Search author on:PubMed Google Scholar

  3. Stavroula Siamoglou
    View author publications

    Search author on:PubMed Google Scholar

  4. Kyriaki Kydonopoulou
    View author publications

    Search author on:PubMed Google Scholar

  5. Anne John
    View author publications

    Search author on:PubMed Google Scholar

  6. Alexandra Gerou
    View author publications

    Search author on:PubMed Google Scholar

  7. Spyridon Gerou
    View author publications

    Search author on:PubMed Google Scholar

  8. Bassam R. Ali
    View author publications

    Search author on:PubMed Google Scholar

  9. Marios Papasotiriou
    View author publications

    Search author on:PubMed Google Scholar

  10. George P. Patrinos
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conceptualization: A.T., G.P.P.; Methodology: A.T., E.M., M.P., G.P.P.; Formal Analysis: A.T., E.M., S.S., A.J., S.G, K.K., A.G.; Resources: B.R.A., M.P., G.P.P.; Writing—Original Draft Preparation: A.T.; Writing—Review and Editing: all authors; Supervision: M.P., G.P.P.; Study Coordination, G.P.P.; All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to George P. Patrinos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Ethics statement

The studies involving human participants were reviewed and approved by the Ethics Committee of the University of Patras (17/03/2017). The patients/participants provided their written informed consent to participate in this study. Αll methods were performed in accordance with the relevant guidelines and regulations.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsironi, A., Mendrinou, E., Siamoglou, S. et al. Combined Role of CYP3A4 and CYP3A5 genetic variants in tacrolimus dose-adjusted trough levels: a clinical retrospective study in kidney transplant patients. Pharmacogenomics J 26, 1 (2026). https://doi.org/10.1038/s41397-025-00395-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41397-025-00395-w

Search

Advanced search

Quick links