Rohatagi S, Hochhaus G, Möllmann H, Barth J, Derendorf H
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainsville, USA.
Pharmazie. 1995 Sep;50(9):610-3.
A problem in the evaluation of pharmacokinetic interactions between prednisolone and cortisol is that both steroids bind to cortisol binding globulin (CBG) and albumin. The binding of both steroids to CBG is saturable in the therapeutic concentration range. General drug binding equations were applied to two drugs and two binding sites and two implicit cubic equations were derived. These equations cannot be solved algebraically. However, the free concentration can be calculated using spreadsheet programs on a personal computer. A spreadsheet for these equations was developed using EXCEL 5.0 and its SOLVER option. Free concentrations of prednisolone and cortisol were determined as a function of total concentrations of both ligands. The simulations show that the protein binding of cortisol remains relatively constant in the physiological range but changes when exogenous corticosteroid is present. However, the degree of protein binding of exogenous corticosteroids that bind to CBG depends on the cortisol concentration which competes for binding sites. At the same time, the exogenous corticosteroid suppresses the release of endogenous cortisol. The presented approach is able to take all of these pharmacokinetic and pharmacodynamic interactions into account leading to a more accurate estimation of active free corticosteroid concentrations.
评估泼尼松龙与皮质醇之间药代动力学相互作用时存在一个问题，即这两种甾体激素均与皮质醇结合球蛋白（CBG）和白蛋白结合。在治疗浓度范围内，这两种甾体激素与CBG的结合是可饱和的。将一般药物结合方程应用于两种药物和两个结合位点，推导得到两个隐式三次方程。这些方程无法用代数方法求解。然而，可使用个人计算机上的电子表格程序计算游离浓度。使用EXCEL 5.0及其求解器选项开发了用于这些方程的电子表格。根据两种配体的总浓度确定了泼尼松龙和皮质醇的游离浓度。模拟结果表明，皮质醇的蛋白结合在生理范围内保持相对恒定，但在外源性皮质类固醇存在时会发生变化。然而，与CBG结合的外源性皮质类固醇的蛋白结合程度取决于竞争结合位点的皮质醇浓度。同时，外源性皮质类固醇会抑制内源性皮质醇的释放。所提出的方法能够考虑所有这些药代动力学和药效学相互作用，从而更准确地估计活性游离皮质类固醇浓度。
