Cattaneo Dario, Perico Norberto, Remuzzi Giuseppe
Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Am J Transplant. 2004 Mar;4(3):299-310. doi: 10.1111/j.1600-6143.2004.00312.x.
One of the main tasks in the management of organ transplantation is the optimization of immunosuppressive therapy, in order to provide therapeutic efficacy limiting drug-related toxicity. In the past years major efforts have been carried out to define therapeutic windows based on blood/plasma levels of each immunosuppressant relating those concentrations to drug dosing and clinical events. Although this traditional approach is able to identify environmental and nongenetic factors that can influence drug exposure during the course of treatment, it presents limitations. Therefore, complementary strategies are advocated. The advent of the genomic era gives birth to pharmacogenomics, a science that studies how the genome as a whole, including single genes as well as gene-to-gene interactions, may affect the action of a drug. This science is of particular importance for drugs characterized by a narrow therapeutic index, such as the immunosuppressants. Preliminary studies focused on polymorphisms of genes encoding for enzymes actively involved in drug metabolism, drug transport and pharmacological target. Pharmacogenomics holds promise for improvement in the ability to individualize immunosuppressive therapy based on the patient's genetic profile, and can be viewed as a support to traditional therapeutic drug monitoring. However, the clinical applicability of this approach is still to be proven.
器官移植管理中的主要任务之一是优化免疫抑制治疗，以在限制药物相关毒性的同时确保治疗效果。在过去几年中，人们付出了巨大努力来确定基于每种免疫抑制剂血液/血浆水平的治疗窗，将这些浓度与药物剂量和临床事件联系起来。尽管这种传统方法能够识别在治疗过程中可能影响药物暴露的环境和非遗传因素，但它也存在局限性。因此，提倡采用补充策略。基因组时代的到来催生了药物基因组学，这是一门研究整个基因组，包括单个基因以及基因间相互作用，如何影响药物作用的科学。对于治疗指数狭窄的药物，如免疫抑制剂，这门科学尤为重要。初步研究聚焦于编码积极参与药物代谢、药物转运和药理靶点的酶的基因多态性。药物基因组学有望提高基于患者基因谱进行免疫抑制治疗个体化的能力，并可被视为对传统治疗药物监测的一种支持。然而，这种方法的临床适用性仍有待证实。
