Pharmacokinetic interaction between endogenous cortisol and exogenous corticosteroids.

Abstract

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.