Influence of Genetic Polymorphisms in CYP3A5, CYP3A4, and MDR1 on Tacrolimus Metabolism after kidney transplantation
Bayanova M. Zhenissova A. Nazarova L. Abdikadirova A. Sapargalieyva M. Malik D. Bolatov A. Abdugafarov S. Assykbayev M. Altynova S. Pya Y.
2024National Scientific Medical Center
Journal of Clinical Medicine of Kazakhstan
2024#21Issue 211 - 17 pp.
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.
genetic polymorphisms , immunosuppressive therapy , kidney transplantation , pharmacogenetics , pharmacokinetics , tacrolimus
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Department of Clinical and Genetic Diagnostics, CAD of Laboratory Medicine, Pathology and Genetics, “University Medical Center” CF, Astana, Kazakhstan
“Medical genetics” Residency program, Department of Clinical and Genetic Diagnostics, CAD of Laboratory Medicine, Pathology and Genetics, “University Medical Center” CF, Astana, Kazakhstan
Shenzhen University Medical School, Shenzhen University, Shenzhen, China
Center for Hepatopancreatobiliary Surgery, Hematology and Organ Transplantation, “National Research Oncology Center”, Astana, Kazakhstan
Organ Transplantation Sector, Center for Hepatopancreatobiliary Surgery, Hematology and Organ Transplantation, “National Research Oncology Center”, Astana, Kazakhstan
“University Medical Center” CF, Astana, Kazakhstan
Department of Clinical and Genetic Diagnostics
“Medical genetics” Residency program
Shenzhen University Medical School
Center for Hepatopancreatobiliary Surgery
Organ Transplantation Sector
“University Medical Center” CF
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