Argudo A, González de Aledo J M, Alía P, Ramírez P, Serrano T, Fabregat J, Castellote J
Toxicology, Labco Diagnostics, Esplugues de Llobregat, Barcelona, Spain.
Laboratori Clínic, Bellvitge-IDIBELL University Hospital, University of Barcelona, L'Hospitalet, Barcelona, Spain.
Transplant Proc. 2015 Oct;47(8):2388-92. doi: 10.1016/j.transproceed.2015.09.024.
The aim of this work was to evaluate the CYP3A5:CYP3A51/CYP3A53 (6986A>G) polymorphism related to the pharmacokinetic characteristics of tacrolimus during the first 3 months after transplantation, analyzing both donor and recipient genotype, in liver transplant patients.
This retrospective, single-center, cohort study included patients who had been treated with tacrolimus monotherapy with or without corticoids (n = 67). Donors and recipients were genotyped for the CYP3A5*3 allele polymorphism (6986A>G) by use of a TaqMan polymerase chain reaction technique. The presence or absence of the *1 allele ("minor-allele") was analyzed for correlation with the tacrolimus dose-normalized ratio during the 3 months after transplantation.
The following observations were obtained in the population studied: (1) Frequency of the minor allele1 was much lower both in recipients (11.9% versus 88.1%) and donors (19.4% versus 80.6%), with no statistically significant differences between both distributions. (2) Recipient genotype for CYP3A51/3-polymorphism had no influence in tacrolimus pharmacokinetics, with no differences between carriers and non-carriers of the minor-allele1. (3) However, from the first month after transplantation, patients with grafts from donor carriers of minor allele*1 had lower concentration-dose ratios compared with patients with grafts from donor non-carriers of that allele (71.1 versus 119.3 and 90.5 versus 126.3, for 30 and 90 days after transplantation, respectively; P < .05).
The presence of the CYP3A5-6986A>G-polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although the difference was statistically significant only for the first month after transplantation. This means that in liver transplant patients receiving grafts from donors carrying the CYP3A5*1-polymorphism, a larger dose of tacrolimus from the first month after transplantation would be needed. The evidence provided in this study showed no effect of the recipient genotype.
本研究旨在评估肝移植患者移植后前3个月与他克莫司药代动力学特征相关的CYP3A5:CYP3A51/CYP3A53（6986A>G）基因多态性，分析供体和受体的基因型。
这项回顾性、单中心队列研究纳入了接受他克莫司单药治疗（联合或不联合皮质类固醇）的患者（n = 67）。采用TaqMan聚合酶链反应技术对供体和受体进行CYP3A53等位基因多态性（6986A>G）基因分型。分析1等位基因（“次要等位基因”）的有无与移植后3个月内他克莫司剂量标准化比值的相关性。
在所研究的人群中获得了以下观察结果：（1）次要等位基因1在受体（11.9%对88.1%）和供体（19.4%对80.6%）中的频率均低得多，两种分布之间无统计学显著差异。（2）CYP3A51/3基因多态性的受体基因型对他克莫司药代动力学无影响，次要等位基因1的携带者和非携带者之间无差异。（3）然而，从移植后第一个月起，与来自次要等位基因1供体非携带者的移植物患者相比，来自次要等位基因1供体携带者的移植物患者的浓度-剂量比值较低（移植后30天和90天分别为71.1对119.3和90.5对126.3；P <.05）。
供体中CYP3A5-6986A>G基因多态性的存在影响受体中他克莫司的药代动力学，尽管仅在移植后第一个月差异具有统计学显著性。这意味着在接受来自携带CYP3A5*1基因多态性供体移植物的肝移植患者中，移植后第一个月起需要更大剂量的他克莫司。本研究提供的证据表明受体基因型无影响。
