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. https://doi.org/10.23950/jcmk/14511
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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.

ABSTRACT

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.
Keywords: Kidney transplantation, tacrolimus, immunosuppressive therapy, genetic polymorphisms, pharmacogenetics, pharmacokinetics

CITATION

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. https://doi.org/10.23950/jcmk/14511

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