Ferraresso Mariano, Tirelli Amedea, Ghio Luciana, Grillo Paolo, Martina Valentina, Torresani Erminio, Edefonti Alberto
Department of Surgical Sciences, University of Milan, Medical School, Milan, Italy.
Pediatr Transplant. 2007 May;11(3):296-300. doi: 10.1111/j.1399-3046.2006.00662.x.
CYP3A enzyme plays a pivotal role in TAC metabolism. The aim of this study was to analyze retrospectively the influence of CYP3A5 gene polymorphism on TAC pharmacokinetics and pharmacodynamics in 30 teenage kidney transplant recipients. TAC dose, trough blood levels, apparent volume of distribution, as well as blood pressure and antihypertensive therapy obtained at different post-transplant periods, were correlated with the corresponding genotype. Despite a therapeutic monitoring strategy, heterozygotes (CYP3A5*1/3) displayed a lower TAC blood concentration compared with homozygotes (CYP3A53/3). Therefore, a two-fold increase of the daily TAC dose was required in the heterozygotes to reach the desired therapeutic target level. A significant group by time interaction effect was present for both variables (repeated measures ANOVA: p = 0.002) meaning a significant different pharmacokinetic response in these two cohorts. Mean blood pressure was also elevated in CYP3A51/*3 recipients despite similar antihypertensive treatment. This was parallel with an elevated apparent volume of distribution of TAC in this group. Thus, the allele-effect was correlated with one of the most common TAC side-effects suggesting a possible influence of CYP3A5 polymorphism on TAC pharmacodynamics. The authors concluded that a pre-emptive CYP3A5 pharmacogenetic screening could contribute to better individualization of TAC therapy.
CYP3A酶在他克莫司（TAC）代谢中起关键作用。本研究的目的是回顾性分析CYP3A5基因多态性对30例青少年肾移植受者TAC药代动力学和药效学的影响。将移植后不同时期获得的TAC剂量、谷血药浓度、表观分布容积以及血压和抗高血压治疗与相应的基因型进行关联分析。尽管采用了治疗监测策略，但杂合子（CYP3A5*1/3）的TAC血药浓度仍低于纯合子（CYP3A53/3）。因此，杂合子需要将每日TAC剂量增加两倍才能达到理想的治疗目标水平。这两个变量均存在显著的组间时间交互效应（重复测量方差分析：p = 0.002），这意味着这两个队列的药代动力学反应存在显著差异。尽管接受了相似的抗高血压治疗，但CYP3A51/*3受者的平均血压也升高了。这与该组中TAC表观分布容积的升高相一致。因此，等位基因效应与TAC最常见的副作用之一相关，提示CYP3A5基因多态性可能对TAC药效学有影响。作者得出结论，前瞻性的CYP3A5药物遗传学筛查有助于更好地实现TAC治疗的个体化。
