Kato H, Usui M, Muraki Y, Tanemura A, Murata Y, Kuriyama N, Azumi Y, Kishiwada M, Mizuno S, Sakurai H, Okuda M, Nakatani K, Isaji S
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Hospital, Mie, Japan.
Transplant Proc. 2016 May;48(4):1087-94. doi: 10.1016/j.transproceed.2016.02.012.
We investigated a long-term association between donor/recipient CYP3A5 polymorphisms, pharmacokinetics of tacrolimus, and recipient outcomes in settings of living donor liver transplantation (LDLT).
From February 2002 to November 2009, 67 couples of donor/recipients with tacrolimus administration, who could be genotyped for CYP3A5*3 and *1, were eligible in this study. We compared the dose-adjusted trough levels (C/D ratio) and dose/weight ratio of tacrolimus at 1 to 36 months postoperatively and recipient prognosis according to donor/recipient CYP3A5 polymorphisms; 11 in 7, 13 in 15, and 33 in 45, based on recipient genotype, and 11 in 1, 13 in 28, and 33 in 38, based on donor genotype.
On the basis of the data from C/D ratio and dose/weight ratio of tacrolimus, the recipients who had *1 allele and/or whose donor had *1allele required significantly high doses of tacrolimus with, compared with those without, all through 3 years after transplantation. These data allowed us to show the importance of not only recipient CYP3A5 polymorphisms but also donor polymorphisms to obtain the target tacrolimus blood concentration. The overall survival rates of the recipients with 11 (5-year survival rate: 28.6%) were significantly unfavorable, which might have been caused by over-immunosuppression, compared with those with 13 (5-year survival rate: 78.8%) and 33 genotype (5-year survival rate: 84.3%).
Immune suppressive therapy with the use of tacrolimus should be tailored on the basis of CYP3A5 genotype, which may reduce the adverse effects and improve graft outcome.
我们研究了活体肝移植（LDLT）中供体/受体CYP3A5基因多态性、他克莫司药代动力学与受体预后之间的长期关联。
2002年2月至2009年11月，本研究纳入67对接受他克莫司治疗且可对CYP3A53和1进行基因分型的供体/受体夫妇。我们根据供体/受体CYP3A5基因多态性比较了术后1至36个月他克莫司的剂量调整谷浓度（C/D比值）和剂量/体重比以及受体预后；根据受体基因型，11型7例，13型15例，33型45例；根据供体基因型，11型1例，13型28例，33型38例。
根据他克莫司C/D比值和剂量/体重比的数据，与没有1等位基因的受体相比，有1等位基因的受体和/或其供体有1等位基因的受体在移植后的3年中都需要显著更高剂量的他克莫司。这些数据使我们能够证明，不仅受体CYP3A5基因多态性，而且供体基因多态性对于获得目标他克莫司血药浓度都很重要。与13型（5年生存率：78.8%）和3*3基因型（5年生存率：84.3%）的受体相比,11型受体的总体生存率（5年生存率：28.6%）明显较差，这可能是由于免疫抑制过度所致。
应根据CYP3A5基因型调整他克莫司免疫抑制治疗方案，这可能会减少不良反应并改善移植效果。
