Tirelli Silvia, Ferraresso Mariano, Ghio Luciana, Meregalli Elisa, Martina Valentina, Belingheri Mirco, Mattiello Camilla, Torresani Emilio, Edefonti Alberto
Laboratory of Clinical Pathology, Maggiore Hospital Policlinico, Mangiagalli and Regina Elena Foundation, IRCCS, Milan, Italy.
Med Sci Monit. 2008 May;14(5):CR251-254.
CYP3A5 gene polymorphism has been shown to influence tacrolimus (TAC) blood concentration and dose requirement in adult kidney transplant patients. The aim was to analyze retrospectively the modification induced by CYP3A5 gene polymorphism on TAC's pharmacokinetic parameters obtained from 26 adolescents receiving TAC as their main immunosuppressive drug.
MATERIAL/METHODS: The adolescent kidney transplant patients were genotyped for CYP3A5*3 and grouped accordingly. TAC dose, blood levels, and dose-normalized TAC blood concentration and volume of distribution obtained at different post-transplant periods during the first post-transplant year were correlated with the corresponding genotype.
During the first three months post-transplant, heterozygotes (CYP3A5*1/3) displayed a lower TAC blood concentration than homozygotes (CYP3A53/3) (at 1 month: 7.8+/-2.1 vs. 13.4+/-6 ng/ml, p=0.007) despite a therapeutic monitoring strategy. Between 3-12 months post-transplant, TAC blood concentration was comparable between the two groups, but a two-fold increase in the daily drug dose was necessary for the heterozygotes (at 6 months: 0.23+/-0.1 vs. 0.13+/-0.06 mg/kg, p=0.04). The dose-normalized TAC concentration [(ng/ml)/(mg/kg)] was significantly lower in patients displaying the CYP3A51/*3 polymorphism (at 2 weeks: 33+/-2.16 vs. 71.1+/-37.8, p=0.01; 6 months: 35.4+/-12.9 vs. 85.2+/-58.9, p=0.01). At the same time, the volume of distribution of the drug in the latter group was distinctly increased for the entire post-transplant year (at 6 months: 1.79+/-0.42 vs. 0.73+/-0.5 l/kg, p=0.001).
The great influence of CYP3A5 on the pharmacokinetics and pharmacodynamics of TAC in young transplant recipients suggests the need for pre-transplant screening of this polymorphism to improve TAC therapy.
CYP3A5基因多态性已被证明会影响成年肾移植患者的他克莫司（TAC）血药浓度和剂量需求。本研究旨在回顾性分析CYP3A5基因多态性对26例接受TAC作为主要免疫抑制药物的青少年患者TAC药代动力学参数的影响。
材料/方法：对青少年肾移植患者进行CYP3A5*3基因分型并分组。将移植后第一年不同时期的TAC剂量、血药浓度、剂量标准化的TAC血药浓度和分布容积与相应基因型进行关联分析。
移植后前三个月，杂合子（CYP3A5*1/3）的TAC血药浓度低于纯合子（CYP3A53/3）（1个月时：7.8±2.1 vs. 13.4±6 ng/ml，p = 0.007），尽管采用了治疗药物监测策略。移植后3至12个月，两组的TAC血药浓度相当，但杂合子的每日药物剂量需要增加两倍（6个月时：0.23±0.1 vs. 0.13±0.06 mg/kg，p = 0.04）。显示CYP3A1/*3多态性的患者中，剂量标准化的TAC浓度[（ng/ml）/（mg/kg）]显著较低（2周时：33±2.16 vs. 71.1±37.8，p = 0.01；6个月时：35.4±12.9 vs. 85.2±58.9，p = 0.01）。同时，在整个移植后一年中，后一组患者的药物分布容积明显增加（6个月时：1.79±0.42 vs. 0.73±0.5 l/kg，p = 0.001）。
CYP3A5对年轻移植受者TAC的药代动力学和药效学有很大影响，提示需要在移植前筛查这种多态性，以改善TAC治疗。
