Calcineurin inhibitors (CNIs), such as cyclosporine A and tacrolimus, are widely used immunosuppressive agents for the prevention of post-transplantation rejection and have improved 1-year graft survival rates by up to 90%. However, CNIs can induce severe reactions, such as acute or chronic allograft nephropathy, hypertension, and neurotoxicity. Because CNIs have varied bioavailabilities, narrow therapeutic ranges, and individual propensities for toxic effects, therapeutic drug monitoring is necessary for all CNIs. Identifying the genetic polymorphisms in drug-metabolizing enzymes will help to determine personalized dosage regimens for CNIs, as CNIs are substrates for CYP3A5 and P-glycoprotein (P-gp, MDR1). CNIs are often concomitantly administered with voriconazole or proton pump inhibitors (PPIs), giving rise to drug interaction problems. Voriconazole and PPIs can increase the blood concentrations of CNIs, and both are primarily metabolized by CYP2C19. Thus, it is expected that interactions between CNIs and voriconazole or PPI would be affected by CYP2C19 and CYP3A5 polymorphisms. CNI-induced acute kidney injury (AKI) is a serious complication of transplantations. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are noninvasive urinary biomarkers that are believed to be highly sensitive to CNI-induced AKI. In this article, we review the adverse events and pharmacokinetics of CNIs and the biomarkers related to CNIs, including CYP3A5, CYP2C19, MDR1, NGAL, and KIM-1. We hope that these data will help to identify the optimal biomarkers for monitoring CNI-based immunosuppressive therapy after organ transplantation.

中文翻译：

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用于在器官移植后使用钙调神经磷酸酶抑制剂进行免疫抑制治疗的个体化剂量调整的生物标志物。

钙调神经磷酸酶抑制剂（CNIs），例如环孢菌素A和他克莫司，被广泛用于预防移植后排斥反应的免疫抑制剂，并提高了90％的一年移植存活率。但是，CNI会引起严重的反应，例如急性或慢性同种异体肾病，高血压和神经毒性。由于CNI具有不同的生物利用度，狭窄的治疗范围以及具有毒性作用的个体倾向，因此对所有CNI都必须进行治疗药物监测。鉴定药物代谢酶中的遗传多态性将有助于确定CNI的个性化剂量方案，因为CNI是CYP3A5和P-糖蛋白（P-gp，MDR1）的底物。CNI通常与伏立康唑或质子泵抑制剂（PPI）并用，从而引起药物相互作用问题。伏立康唑和PPI可增加CNI的血药浓度，且两者主要通过CYP2C19代谢。因此，预期CNI与伏立康唑或PPI之间的相互作用将受到CYP2C19和CYP3A5多态性的影响。CNI诱发的急性肾损伤（AKI）是移植的严重并发症。中性粒细胞明胶酶相关的脂蛋白（NGAL）和肾损伤分子1（KIM-1）是非侵入性尿液生物标志物，被认为对CNI诱导的AKI高度敏感。在本文中，我们综述了CNI的不良事件和药代动力学以及与CNI相关的生物标记，包括CYP3A5，CYP2C19，MDR1，NGAL和KIM-1。我们希望这些数据将有助于确定最佳的生物标志物，以监测器官移植后基于CNI的免疫抑制治疗。