Fisher L E, Ludwig E A, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo.
J Pharmacokinet Biopharm. 1992 Aug;20(4):319-31. doi: 10.1007/BF01062461.
A two-compartment closed model was used to characterize the cell trafficking behavior of helper T cells in response to various single doses of methylprednisolone. Steroids are assumed to inhibit the circadian-determined cell return from extravascular sites to blood in a classic inhibitory pattern reflected by an IC50. The rate of cell efflux from tissues is modeled with a cosine function having a period of 24 hr and a maximum at about 1 AM. Nonlinear least-squares regression employing differential equations was used to analyze helper T-cell data from three human studies from our laboratory. The IC50 value of methylprednisolone of 12-19 ng/ml approximates receptor KD values. Simulations were performed to demonstrate the log-linear role of steroid dose or AUC on the integral of effect of helper T cells over a wide range of methylprednisolone doses. This pharmacodynamic model allows flexibility for characterizing any type of steroid dosing regimen and is relevant in describing complex response data for corticosteroid immunosuppressive effects in man.
采用二室封闭模型来表征辅助性T细胞在不同单剂量甲泼尼龙作用下的细胞转运行为。假定类固醇以IC50反映的经典抑制模式抑制昼夜节律决定的细胞从血管外部位返回血液。组织中细胞流出率用周期为24小时且在凌晨1点左右达到最大值的余弦函数进行建模。使用微分方程的非线性最小二乘回归分析了我们实验室三项人体研究中的辅助性T细胞数据。甲泼尼龙的IC50值为12 - 19 ng/ml，接近受体KD值。进行模拟以证明在广泛的甲泼尼龙剂量范围内，类固醇剂量或AUC对辅助性T细胞效应积分的对数线性作用。该药效学模型为表征任何类型的类固醇给药方案提供了灵活性，并且在描述人体皮质类固醇免疫抑制作用的复杂反应数据方面具有相关性。
