Necker Hospital & Paris Descartes University, 149, rue de Sèvres, 75015, Paris, France.
Pharmacogenomics. 2010 Oct;11(10):1491-501. doi: 10.2217/pgs.10.137.
The calcineurin inhibitors ciclosporin and tacrolimus are used to prevent acute rejection of solid organs after transplantation. Their use can lead to chronic renal damage characterized by progressive and irreversible deterioration of renal function associated with interstitial fibrosis, tubular atrophy, arteriolar hyalinosis and glomerulosclerosis. Many approaches to better understand the mechanisms of this toxicity are in use. The aim of these approaches is to find biomarkers of early kidney injury and potential therapeutic targets. Despite these efforts, the biological processes leading to calcineurin inhibitor nephrotoxicity remain poorly understood. Furthermore, the diagnosis of chronic renal damage remains inaccurate without definitive diagnostic tools, no effective prevention exists and a therapy to treat the damage has yet to be developed. In this article, theories of pharmacodynamics, pharmacokinetics, therapeutic drug monitoring and pharmacogenetics are synthesized in ways that may improve the understanding of mechanisms leading to calcineurin inhibitor toxicity. The importance of global approaches such as toxicogenomics is emphasized to characterize early cellular responses implicated in calcineurin inhibitor nephrotoxicity.
钙调磷酸酶抑制剂环孢素和他克莫司被用于预防实体器官移植后的急性排斥反应。它们的使用会导致慢性肾损伤，其特征是肾功能进行性和不可逆转恶化，伴有间质纤维化、肾小管萎缩、小动脉玻璃样变性和肾小球硬化。目前有许多方法可用于更好地了解这种毒性的机制。这些方法的目的是寻找早期肾损伤的生物标志物和潜在的治疗靶点。尽管做出了这些努力，但导致钙调磷酸酶抑制剂肾毒性的确切生物学过程仍知之甚少。此外，如果没有明确的诊断工具，慢性肾损伤的诊断仍然不准确，也没有有效的预防措施，而且还没有开发出治疗损伤的方法。在本文中，药理学、药代动力学、治疗药物监测和药物遗传学的理论被综合起来，以期更好地理解导致钙调磷酸酶抑制剂毒性的机制。强调了毒理学基因组学等整体方法的重要性，以描述涉及钙调磷酸酶抑制剂肾毒性的早期细胞反应。
