Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, E-50830 Villanueva de Gállego, Zaragoza, Spain.
Int J Mol Sci. 2024 Oct 21;25(20):11327. doi: 10.3390/ijms252011327.
Tacrolimus (TAC) is a commonly used immunosuppressive drug in solid organ transplantation. Pharmacogenetics has been demonstrated before to be decisive in TAC pharmacotherapy. The variant has been reported to be the main determinant of TAC dose requirements; however, other polymorphisms have also proven to be influential, especially in CYP3A5 non-expressor patients. The aim of this study is to evaluate the influence of genetic polymorphisms in TAC therapy in a cohort of Spanish transplant recipients. Genetic analysis including ten polymorphic variants was performed, and demographic and clinical data and pharmacotherapy of 26 patients were analyzed. No significant differences were found in weight-adjusted dose between CYP3A5 expressors and non-expressors (0.047 mg/kg vs. 0.044 mg/kg), while they were found for carriers of the allele (0.101 mg/kg; < 0.05). The results showed that patients with at least one allele had a higher TAC dose and lower blood concentration. Dose-adjusted TAC blood levels were also lower in carriers compared to non-carriers (0.72 ng/mL/mg vs. 2.88 ng/mL/mg). These results support the independence of and variants as determinants of dose requirements despite the linkage disequilibrium present between the two. The variability in genotype frequency between ethnicities may be responsible for the discrepancy found between studies.
他克莫司（TAC）是实体器官移植中常用的免疫抑制剂。之前的研究表明，药物遗传学在 TAC 药物治疗中起决定性作用。该变体已被报道是 TAC 剂量需求的主要决定因素；然而，其他多态性也被证明具有影响力，尤其是在 CYP3A5 非表达者患者中。本研究旨在评估在西班牙移植受者队列中遗传多态性对 TAC 治疗的影响。进行了包括十个多态性变体的基因分析，并分析了 26 名患者的人口统计学和临床数据以及药物治疗情况。在 CYP3A5 表达者和非表达者之间，体重校正剂量没有差异（0.047mg/kg 与 0.044mg/kg），而在 等位基因携带者之间存在差异（0.101mg/kg；<0.05）。结果表明，至少携带一个 等位基因的患者 TAC 剂量更高，血药浓度更低。与非携带者相比， 携带者的剂量校正 TAC 血药浓度也更低（0.72ng/mL/mg 与 2.88ng/mL/mg）。这些结果支持 和 变体作为剂量需求决定因素的独立性，尽管两者之间存在连锁不平衡。不同种族之间基因型频率的差异可能是导致研究结果差异的原因。
