Division of Clinical Sciences: Renal Medicine, St. George's, University of London, London, UK.
Clin Chim Acta. 2012 Sep 8;413(17-18):1312-7. doi: 10.1016/j.cca.2011.10.013. Epub 2011 Oct 18.
The immunosuppressive drugs used for solid organ transplantation all have a narrow therapeutic index with wide variation between individuals in the blood concentration achieved by a given dose. Therapeutic drug monitoring is employed routinely but may not allow optimisation of drug exposure during the critical period two to three days following transplantation. A key factor in the inter-individual variability for tacrolimus, and probably sirolimus, is whether an individual is genetically predicted to express the drug metabolising enzyme cytochrome P450 3A5 (CYP3A5). Individuals predicted to express CYP3A5 by possession of at least one wild-type CYP3A51 allele require 1.5-2 times higher doses of tacrolimus to achieve target blood concentrations than individuals homozygous for the CYP3A53 allele who are functional non-expressers of CYP3A5. Planning the initial tacrolimus dose based on the CYP3A5 genotype has been shown to allow more rapid achievement of target blood concentrations after transplantation than a standard dose given to all patients. However, it remains to be demonstrated that use of this approach as an adjunct to therapeutic drug monitoring can reduce either efficacy failure (transplant rejection) or toxicity. Use of a pharmacogenetic approach to dosing sirolimus awaits testing and it is unlikely to be useful for ciclosporin or everolimus.
用于实体器官移植的免疫抑制药物的治疗指数均较窄，在给予特定剂量时，个体间的血药浓度差异很大。常规进行治疗药物监测，但在移植后 2 至 3 天的关键时期，可能无法优化药物暴露。他克莫司和（可能）西罗莫司个体间变异性的一个关键因素是个体是否具有预测表达药物代谢酶细胞色素 P450 3A5（CYP3A5）的遗传特征。预测携带至少一个野生型 CYP3A51 等位基因的个体需要 1.5-2 倍高的他克莫司剂量才能达到目标血药浓度，而 CYP3A53 等位基因纯合子的个体为 CYP3A5 的功能性非表达者。基于 CYP3A5 基因型规划初始他克莫司剂量已被证明可在移植后比所有患者给予标准剂量更快地达到目标血药浓度。然而，仍需要证明这种方法作为治疗药物监测的辅助手段可以降低疗效失败（移植排斥）或毒性的风险。西罗莫司的药物遗传学剂量方法的应用尚待测试，对于环孢素或依维莫司可能没有用。
