Medical Pharmacology Department, Faculty of Medicine Cairo University, Cairo, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Taibah University, Madinah, Saudi Arabia.
J Clin Lab Anal. 2023 Oct;37(19-20):e24969. doi: 10.1002/jcla.24969. Epub 2023 Oct 3.
Tacrolimus (TAC) is the mainstay of immunosuppressive regimen for kidney transplantations. Its clinical use is complex due to high inter-individual variations which can be partially attributed to genetic variations at the metabolizing enzymes CYP3A4 and CYP3A5. Two single nucleotide polymorphisms (SNPs), CYP3A422 and CYP3A53, have been reported as important causes of differences in pharmacokinetics that can affect efficacy and/or toxicity of TAC.
Investigating the effect of CYP3A422 and CYP3A53 SNPs individually and in combination on the TAC concentration in Egyptian renal recipients.
Overall, 72 Egyptian kidney transplant recipients were genotyped for CYP3A422 G>A and CYP3A53 T>C. According to the functional defect associated with CYP3A variants, patients were clustered into: poor (PM) and non-poor metabolizers (Non-PM). The impact on dose adjusted through TAC concentrations (C0) and daily doses at different time points after transplantation was evaluated.
Cyp3A41/22 and PM groups require significantly lower dose of TAC (mg/kg) at different time points with significantly higher concentration/dose (C0/D) ratio at day 10 in comparison to Cyp3A41/1 and Non-PM groups respectively. However, CyP3A53 heterozygous individuals did not show any significant difference in comparison to CyP3A51/*3 individuals. By comparing between PM and Non-PM, the PM group had a significantly lower rate of recipients not reaching target C0 at day 14.
This is the first study on Egyptian population to investigate the impact of CYP3A422 and CYP3A53 SNPs individually and in combination on the TAC concentration. This study and future multicenter studies can contribute to the individualization of TAC dosing in Egyptian patients.
他克莫司（TAC）是肾移植免疫抑制方案的主要药物。由于个体间差异较大，其临床应用较为复杂，这种差异部分归因于代谢酶 CYP3A4 和 CYP3A5 的遗传变异。已有报道称，两个单核苷酸多态性（SNP），即 CYP3A422 和 CYP3A53，是导致药代动力学差异的重要原因，这种差异可能会影响 TAC 的疗效和/或毒性。
单独和联合研究 CYP3A422 和 CYP3A53 SNP 对埃及肾移植受者 TAC 浓度的影响。
总共对 72 例埃及肾移植受者的 CYP3A422 G>A 和 CYP3A53 T>C 进行基因分型。根据与 CYP3A 变体相关的功能缺陷，患者分为：弱代谢型（PM）和非弱代谢型（Non-PM）。评估 CYP3A 变体对移植后不同时间点 TAC 浓度（C0）和日剂量的调整剂量的影响。
与 Cyp3A41/1 和 Non-PM 组相比，Cyp3A41/22 和 PM 组在不同时间点需要的 TAC（mg/kg）剂量明显更低，且在第 10 天的浓度/剂量（C0/D）比值明显更高。然而，Cyp3A53 杂合子个体与 Cyp3A51/*3 个体相比，无任何显著差异。将 PM 组与 Non-PM 组进行比较，PM 组在第 14 天未达到靶 C0 的受者比例明显更低。
这是第一项针对埃及人群的研究，旨在单独和联合研究 CYP3A422 和 CYP3A53 SNP 对 TAC 浓度的影响。本研究和未来的多中心研究可以为埃及患者 TAC 剂量个体化提供依据。
