Therapeutic drug monitoring of cyclosporine and tacrolimus
Therapeutic drug monitoring of cyclosporine and tacrolimus
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DOI：
10.1016/s0009-9120(98)00049-6
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发表时间：
1998-07-01
影响因子：
2.8
通讯作者：
Shaw, LM
中科院分区：
文献类型：
--
作者：
Oellerich, M;Armstrong, VW;Shaw, LM
本文的目的是对 1995 年举行的路易斯湖他克莫司和环孢素 (CsA) 监测共识会议上制定的建议和指南进行批判性评估和更新 (1, 2)。他克莫司和 CsA 监测的关键问题包括分析方法的特异性要求、药代动力学监测（波谷水平与简略 AUC）、时间依赖性治疗范围、伴随免疫抑制药物（如霉酚酸）的影响，以及 CsA 的微乳制剂对治疗窗的影响。药效学监测是另一个重要的话题。需要能够测量个体患者的免疫抑制状态和代谢物的免疫抑制贡献的测试系统。尽管 CsA 和他克莫司具有不同的分子结构，但它们的免疫抑制特性和分子机制非常相似 (3)。这两种药物都在细胞内与丰富的胞浆蛋白（称为亲免素）结合。就他克莫司而言，主要结合蛋白似乎是 FK BP 12，而 CsA 与称为亲环蛋白的亲免蛋白家族结合。然后，这些药物-免疫亲和素复合物可以与钙调磷酸酶-钙调蛋白-钙形成五聚体复合物，引起钙调磷酸酶-磷酸酶活性的非竞争性抑制。后一种活性对于激活细胞质核因子（例如 NFAT）是必需的，然后 NFAT 转位到细胞核并激活细胞因子转录（例如 IL-2），这是 T 细胞激活的关键步骤。
The purpose of this article is to present a critical appraisal and update of the recommendations and guidelines established at the Lake Louise Consensus Conferences on tacrolimus and cyclosporine (CsA) monitoring held in 1995 (1, 2). The critical issues for tacrolimus and CsA monitoring include specificity requirements for analytical methods, pharmacokinetic monitoring (trough levels vs. abbreviated AUC), time-dependent therapeutic ranges, influence of concomitant immunosuppressive drugs (such as mycophenolic acid), and, in the case of CsA, of the microemulsion formulation on the therapeutic window. Pharmacodynamic monitoring is an additional important topic. Test systems are required that are capable of measuring the individual patient’s state of immunosuppression and the immunosuppressive contribution of metabolites. Although CsA and tacrolimus have different molecular structures, their immunosuppressive properties and molecular mechanisms are remarkably similar (3). Both drugs bind intracellularly to abundant cytosolic proteins known as immunophilins. In the case of tacrolimus, the major binding protein appears to be FK BP 12, while CsA binds to a family of immunophilins called cyclophilins. These drug-immunophilin complexes can then form a pentameric complex with calcineurin-calmodulin-calcium causing a non-competitive inhibition of calcineurin-phosphatase activity. The latter activity is necessary for activation of cytoplasmic nuclear factors such as NFAT which then translocate to the nucleus and activate cytokine transcription (eg, IL-2) a critical step in T-cell activation.