The influence of UGT polymorphisms as biomarkers in solid organ transplantation.
The influence of UGT polymorphisms as biomarkers in solid organ transplantation.
复制标题
UGT多态性作为固体器官移植中的生物标志物的影响。
DOI：
10.1016/j.cca.2012.01.031
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发表时间：
2012-09-08
期刊：
影响因子：
--
通讯作者：
Innocenti F
中科院分区：
文献类型：
--
作者：
Dupuis R;Yuen A;Innocenti F
在实体器官移植患者中，在预防排斥反应和减少不良反应之间保持良好的平衡是很重要的。几种免疫抑制剂，如他克莫司、环孢素、西罗莫司和伊波利莫斯，需要治疗药物监测。对基因组生殖系变异的研究为个体化治疗打开了新的机会。在目前可用的免疫抑制剂中，环孢素、他克莫司和霉酚酸是UGT1A和2B家族葡萄糖醛酸化酶的体外底物。霉酚酸，以霉酚酸酯或霉酚酸钠的形式给药，是最常用的抗增殖免疫抑制剂。霉酚酸是一种在肠壁、血液、肝脏和组织中迅速脱酯的前体药物，其活性部分为霉酚酸(MPA)。甲孕酮对多种代谢物有显著的肝脏代谢作用。7-羟基葡萄糖醛酸苷是主要的代谢物，没有活性。本文综述了胚系UGT变异与霉酚酸的药代动力学和药效学的遗传关联的研究现状。我们对到目前为止进行的研究的结论评估是，这些胚系标记物还没有准备好在临床上用于个性化霉酚酸的剂量和改善结果。需要新的方法来确定影响移植结果的新的基因决定因素。
In solid organ transplant patients, it is important to maintain a fine balance between preventing rejection and reducing adverse effects. Several immunosuppressive agents such tacrolimus, cyclosporine, sirolimus and everolimus require therapeutic drug monitoring. The study of germline variation of the genome has opened novel opportunities to individualize therapy. Among the currently available immunosuppressive agents, cyclosporine, tacrolimus and mycophenolic acid are in vitro substrates of the UGT1A and 2B families of glucuronidation enzymes. Mycophenolic acid, either given as mycophenolate mofetil or mycophenolate sodium, is the most frequently used antiproliferative immunosuppressant. Mycophenolic acid is a prodrug which is rapidly de-esterified in the gut wall, blood, liver and tissue to the active moiety, mycophenolic acid (MPA). MPA undergoes significant hepatic metabolism to several metabolites. The 7-hydroxyglucuronide MPA is the major metabolite and is inactive. This paper reviews the current status of the genetic associations between germline UGT variants and the pharmacokinetics and pharmacodynamics of mycophenolic acid. Our conclusive assessment of the studies conducted so far is that these germline markers are not ready to be used in the clinic to individualize mycophenolic acid dosing and improve outcome. Novel approaches are required to identify new genetic determinants of outcomes in transplantation.
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