Pharmacokinetics of total and unbound prednisone and prednisolone in stable kidney transplant recipients with diabetes mellitus.
Pharmacokinetics of total and unbound prednisone and prednisolone in stable kidney transplant recipients with diabetes mellitus.
复制标题
稳定的肾脏移植受者的总泼尼松和泼尼松龙的药代动力学。
DOI：
10.1097/ftd.0000000000000045
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发表时间：
2014-08
影响因子：
2.5
通讯作者：
Akhlaghi F
中科院分区：
文献类型：
--
作者：
Ionita IA;Ogasawara K;Gohh RY;Akhlaghi F
皮质类固醇泼尼松是移植后免疫抑制治疗的重要组成部分。泼尼松或其药理活性代谢物泼尼松龙的药代动力学参数在移植受者中尚未得到很好的表征。本研究的目的是比较糖尿病和非糖尿病稳定肾移植受者中总的和未结合的泼尼松和泼尼松龙的药代动力学，并评估影响泼尼松龙血浆蛋白结合的因素。在 20 名糖尿病稳定肾移植受者和 18 名非糖尿病稳定肾移植受者中获得了泼尼松和泼尼松龙浓度-时间曲线，每天口服 5-10 毫克泼尼松。除了药物和代谢物暴露之外，还使用非线性混合效应建模方法评估了影响泼尼松龙蛋白结合的因素。该模型考虑了泼尼松龙和皮质醇以可饱和方式与皮质类固醇结合球蛋白（CBG）的结合以及泼尼松龙以非饱和方式与白蛋白的结合。最后，我们研究了几个协变量（包括糖尿病、葡萄糖浓度、血红蛋白 A1c、肌酐清除率、体重指数、性别、年龄和移植后时间）对皮质类固醇及其结合蛋白之间的亲和常数 (K) 的影响。在糖尿病患者中，总泼尼松龙和未结合泼尼松龙的浓度-时间曲线下剂量标准化面积值分别高出 27% 和 23%。此外，糖尿病受试者中总泼尼松龙与泼尼松浓度（活性/非活性形式）的比率较高（P <0.001）。蛋白质结合建模结果显示，CBG-泼尼松龙 (KCBG,PL) 的亲和常数与患者的性别和糖尿病状况相关。较高的泼尼松龙暴露可能会导致糖尿病肾移植受者发生皮质类固醇相关并发症的风险增加。
The corticosteroid prednisone is an important component of post transplantation immunosuppressive therapy. Pharmacokinetic parameters of prednisone or its pharmacologically active metabolite, prednisolone, are not well characterized in transplant recipients. The objective of the present study was to compare the pharmacokinetics of total and unbound prednisone and prednisolone in diabetic and nondiabetic stable kidney transplant recipients and to evaluate the factors influencing plasma protein binding of prednisolone. Prednisone and prednisolone concentration-time profiles were obtained in 20 diabetic and 18 nondiabetic stable kidney transplant recipients receiving an oral dose of 5-10 mg prednisone per day. In addition to drug and metabolite exposures, factors influencing prednisolone protein binding were evaluated using a nonlinear mixed effects modeling approach. This model takes into account binding of prednisolone and cortisol to Corticosteroid Binding Globulin (CBG) in a saturable fashion and binding of prednisolone to albumin in a non-saturable fashion. Finally, we have investigated the influence of several covariates including diabetes, glucose concentration, hemoglobin A1c, creatinine clearance, body mass index, gender, age and time post transplantation on the affinity constant (K) between corticosteroids and their binding proteins. In diabetic patients, the values of dose-normalized area under the concentration-time curves were 27% and 23% higher for total and unbound prednisolone, respectively. Moreover, the ratio of total prednisolone to prednisone concentrations (active /inactive forms) was higher in diabetic subjects (P <0.001). Modeling protein binding results revealed that the affinity constant of CBG-prednisolone (KCBG,PL) was related to patient's gender and diabetes status. Higher prednisolone exposure could potentially lead to the increased risk of corticosteroid related complications in diabetic kidney transplant recipients.