University of Queensland School of Pharmacy, Pharmacy Australia Centre of Excellence, 20 Cornwall St., Woolloongabba, Brisbane, QLD, 4102, Australia.
Clin Pharmacokinet. 2012 Nov;51(11):711-41. doi: 10.1007/s40262-012-0007-8.
Prednisolone and prednisone are integral components of induction and maintenance immunosuppressive regimens in solid organ transplantation. The pharmacokinetics of these agents are extremely complex. Prednisolone is the active drug moiety while prednisone is both a pro-drug and inactive metabolite of prednisolone. Within the dosage range used in transplantation, prednisolone and prednisone exhibit concentration-dependent non-linear pharmacokinetics when parameters are measured with reference to total drug concentration. Dose dependency disappears when free (unbound) prednisolone is measured. Altered organ function, changing biochemistry and use of a number of concomitant medicines in transplantation appear to lead to pharmacokinetic differences in transplant recipients compared with other patient groups. Greater than threefold variability in dose-adjusted exposure to total prednisolone in transplant recipients is evident. Time post-transplant, hepatic and renal dysfunction, patient age, sex, bodyweight, serum albumin concentration, concomitant medication exposure, various disease states and genetic polymorphisms in metabolic enzymes and drug transporters have sometimes been associated with prednisolone pharmacokinetic variability. The clinical impact of corticosteroid therapy on the disposition of ciclosporin, tacrolimus and sirolimus and the impact of different immunosuppressant therapy combinations on prednisolone exposure needs to be further elucidated. Patient response patterns to prednisolone are consistent with delayed and indirect mechanisms of corticosteroid action involving modification of nuclear transcription and protein synthesis. Many adverse effects have been linked with prednisolone and prednisone therapy, but not all of these have been investigated thoroughly in transplant populations. Dyslipidaemia, growth restriction, diabetogenesis, hypertension and cataracts are well studied toxicities. Evidence is less clear for prednisolone-induced osteonecrosis, obesity and hypertriglyceridaemia. There have been some reports of a relationship between prednisolone pharmacokinetics and incidence of acute rejection, Cushing's syndrome and adverse cardiovascular and metabolic events. Dosing of prednisolone and prednisone in transplantation is typically empirical and varies significantly across transplant centres. Currently, authoritative guidelines are conflicting in their opinions regarding corticosteroid avoidance and early discontinuation in adult kidney transplantation. Overall, data suggest the promise of corticosteroid-free immunosuppression in paediatric patients. Further investigation of the pharmacokinetics and pharmacodynamics of prednisolone and prednisone in transplant recipients based on new chromatography assay techniques and free drug measurement, population pharmacokinetic/pharmacodynamic modelling approaches, genetic testing and larger studies in patients on modern day immunosuppressant protocols may lead to better individualization of corticosteroid therapy in the future.
泼尼松龙和泼尼松是实体器官移植中诱导和维持免疫抑制方案的重要组成部分。这些药物的药代动力学极其复杂。泼尼松龙是活性药物部分，而泼尼松既是泼尼松龙的前药，也是其无活性的代谢物。在移植中使用的剂量范围内，当根据总药物浓度测量参数时，泼尼松龙和泼尼松表现出浓度依赖性的非线性药代动力学。当测量游离（未结合）泼尼松龙时，剂量依赖性消失。器官功能改变、生化变化以及移植中使用的许多伴随药物似乎导致移植受者的药代动力学与其他患者群体不同。在移植受者中，总泼尼松龙的剂量调整后暴露量的变异性大于三倍。移植后时间、肝肾功能障碍、患者年龄、性别、体重、血清白蛋白浓度、伴随药物暴露、各种疾病状态以及代谢酶和药物转运体的遗传多态性有时与泼尼松龙药代动力学的变异性有关。皮质类固醇治疗对环孢素、他克莫司和西罗莫司处置的影响以及不同免疫抑制剂治疗组合对泼尼松龙暴露的影响需要进一步阐明。泼尼松龙治疗的患者反应模式与皮质类固醇作用的延迟和间接机制一致，涉及核转录和蛋白质合成的修饰。许多不良反应与泼尼松龙和泼尼松治疗有关，但并非所有这些不良反应都在移植人群中进行了彻底研究。血脂异常、生长受限、糖尿病发生、高血压和白内障是研究得很好的毒性作用。泼尼松龙引起的骨坏死、肥胖和高三酰甘油血症的证据不太明确。有一些关于泼尼松龙药代动力学与急性排斥反应、库欣综合征和不良心血管和代谢事件发生率之间关系的报告。在移植中，泼尼松龙和泼尼松的剂量通常是经验性的，并且在移植中心之间差异很大。目前，权威指南在成人肾移植中关于皮质类固醇的避免和早期停用的意见存在冲突。总体而言，数据表明在儿科患者中实现无皮质类固醇免疫抑制的前景。基于新的色谱分析技术和游离药物测量、群体药代动力学/药效动力学建模方法、基因检测以及现代免疫抑制剂方案患者的更大研究，进一步研究泼尼松龙和泼尼松在移植受者中的药代动力学和药效动力学，可能会导致未来皮质类固醇治疗的个体化更好。
