Ladd Alexandra D, Angeli-Pahim Isabella, Lewis Duncan, Warren Curtis, Nittu Satyavardhan, Lamba Jatinder, Duarte Sergio, Zarrinpar Ali
Department of Surgery, College of Medicine, University of Florida, PO Box 100118, Gainesville, FL, 32608, USA.
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Sci Rep. 2025 Jul 2;15(1):23508. doi: 10.1038/s41598-025-09296-1.
This study examines the influence of single nucleotide polymorphisms in drug metabolizing enzymes CYP3A4, CYP3A5, and UGT1A4, and the transporter ABCB1 on tacrolimus dose requirements and blood trough level variability in the period immediately after liver transplantation. We analyzed genotypes for these genes in 61 adult liver transplant recipients who received tacrolimus and their respective donors. Significant findings include increased average daily deviation (ADD) from the therapeutic range in patients with: donor CYP3A422 GG (1.68 [1.01, 2.29] versus 0.68 [0.42, 1.46] ng/mL/day, p = 0.016), recipient ABCB1 rs2032582 CT/TT (2.07 [1.68, 2.39] versus 1.37 [0.76, 1.95] ng/mL/day , p = 0.013), and donor UGT1A43 TT (1.69 [1.02, 2.42] versus 1.33 [0.54, 1.79] ng/mL/day , p = 0.043). Additionally, higher tacrolimus concentration/weight-adjusted dose ratios [C/D ratio, (ng/mL)/(mg/kg/d)] were observed in recipients with CYP3A41B rs2740574 genotype TT (77.5 [60.7, 143.8] versus 47.5 [26.3, 64.0] (ng/mL)/(mg/kg/d), p = 0.0001), or CYP3A53 rs776746 genotype GG (74.9 [55.7, 147.4] versus 59.3 [36.1, 79.0] (ng/mL)/(mg/kg/d), p = 0.011), and in donor livers with CYP3A4*22 genotype GA/AA (131.5 [86.2, 187.1] versus 68.2 [47.1, 108.7] (ng/mL)/(mg/kg/d), p = 0.028). These findings demonstrate that genetic polymorphisms in both donor and recipient significantly affect tacrolimus dose requirements and the ability to maintain the target therapeutic tacrolimus levels in the immediate post-transplant period, emphasizing the role of precision medicine in optimizing immunosuppression therapeutic drug dosing.
本研究考察了药物代谢酶CYP3A4、CYP3A5和UGT1A4以及转运体ABCB1中的单核苷酸多态性对肝移植术后即刻他克莫司剂量需求和血药谷浓度变异性的影响。我们分析了61例接受他克莫司治疗的成年肝移植受者及其各自供体的这些基因的基因型。重要发现包括：供体CYP3A422 GG基因型患者的治疗范围平均日偏差（ADD）增加（1.68 [1.01, 2.29] 对比0.68 [0.42, 1.46] ng/mL/天，p = 0.016）；受者ABCB1 rs2032582 CT/TT基因型患者的治疗范围平均日偏差增加（2.07 [1.68, 2.39] 对比1.37 [0.76, 1.95] ng/mL/天，p = 0.013）；供体UGT1A43 TT基因型患者的治疗范围平均日偏差增加（1.69 [1.02, 2.42] 对比1.33 [0.54, 1.79] ng/mL/天，p = 0.043）。此外，在CYP3A41B rs2740574基因型为TT的受者中观察到更高的他克莫司浓度/体重校正剂量比 [C/D比，(ng/mL)/(mg/kg/d)]（77.5 [60.7, 143.8] 对比47.5 [26.3, 64.0] (ng/mL)/(mg/kg/d)，p = 0.0001），或在CYP3A53 rs776746基因型为GG的受者中观察到更高的他克莫司浓度/体重校正剂量比 [C/D比，(ng/mL)/(mg/kg/d)]（74.9 [55.7, 147.4] 对比59.3 [36.1, 79.0] (ng/mL)/(mg/kg/d)，p = 0.011），以及在CYP3A4*22基因型为GA/AA的供体肝脏中观察到更高的他克莫司浓度/体重校正剂量比 [C/D比，(ng/mL)/(mg/kg/d)]（131.5 [86.2, 187.1] 对比68.2 [47.1, 108.7] (ng/mL)/(mg/kg/d)，p = 0.028）。这些发现表明，供体和受者的基因多态性均显著影响肝移植术后即刻他克莫司的剂量需求以及维持目标治疗性他克莫司水平的能力，强调了精准医学在优化免疫抑制治疗药物剂量方面的作用。
