Quteineh Lina, Verstuyft Céline, Furlan Valerie, Durrbach Antoine, Letierce Alexia, Ferlicot Sophie, Taburet Anne-Marie, Charpentier Bernard, Becquemont Laurent
Pharmacology Department, Pierre et Marie Curie University, Saint Antoine University Hospital, Paris, France.
Basic Clin Pharmacol Toxicol. 2008 Dec;103(6):546-52. doi: 10.1111/j.1742-7843.2008.00327.x.
Tacrolimus is a widely used immunosuppressive drug in organ transplantation. Its oral bioavailability varies greatly between individuals, and it is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein. Our objective was to determine the influence of CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus daily requirements and on transplantation outcome. One hundred and thirty-six renal graft recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), ABCB1 exon26 (3435C>T) and exon21 (2677G>T/A) single nucleotide polymorphisms. Genotypes were correlated to tacrolimus daily dose at 1-week, 1-, 6- and 12-month post-transplantation and with transplantation outcome. At 1-month post-transplantation, tacrolimus daily dose was higher for patients with CYP3A51/1 genotype compared to CYP3A53/3 genotype (0.26 +/- 0.03 versus 0.16 +/- 0.01 mg/kg/day, respectively, P < 0.0001). Similar results were obtained at 6- and 12-month post-transplantation. Furthermore, CYP3A51 homozygotes were associated with increased risk of acute rejection episodes compared to patients with CYP3A51/3 and CYP3A53/*3 genotypes (38% versus 10% and 9%, respectively, P = 0.01). CYP3A5 genetic polymorphism was not associated with tacrolimus-related nephrotoxicity. ABCB1 polymorphisms were not related with transplantation outcome. CYP3A5 genetic polymorphism appeared in our study to affect tacrolimus daily dose requirements and transplantation outcome. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression.
他克莫司是器官移植中广泛使用的免疫抑制药物。其口服生物利用度在个体间差异很大，并且它是细胞色素P450 3A（CYP3A）和P-糖蛋白的底物。我们的目的是确定CYP3A5和ABCB1基因多态性对他克莫司每日需求量及移植结局的影响。对136例接受他克莫司治疗的肾移植受者进行CYP3A5（6986A>G）、ABCB1外显子26（3435C>T）和外显子21（2677G>T/A）单核苷酸多态性的基因分型。将基因型与移植后1周、1个月、6个月和12个月时他克莫司的每日剂量以及移植结局进行关联分析。移植后1个月时，CYP3A5*1/1基因型患者的他克莫司每日剂量高于CYP3A53/3基因型患者（分别为0.26±0.03与0.16±0.01mg/kg/天，P<0.0001）。在移植后6个月和12个月时也获得了类似结果。此外，与CYP3A51/3和CYP3A53/3基因型患者相比，CYP3A51纯合子发生急性排斥反应的风险增加（分别为38%、10%和9%，P=0.01）。CYP3A5基因多态性与他克莫司相关的肾毒性无关。ABCB1多态性与移植结局无关。在我们的研究中，CYP3A5基因多态性似乎会影响他克莫司的每日剂量需求和移植结局。移植前筛查这种单核苷酸多态性可能有助于选择合适的初始每日剂量并实现理想免疫抑制。
