PHARMACOKINETIC INTERACTION BETWEEN ENDOGENOUS CORTISOL AND EXOGENOUSCORTICOSTEROIDS

A problem in the evaluation of pharmacokinetic interactions between pr ednisolone and cortisol is that both steroids bind to cortisol binding globulin (CBG) and albumin. The binding of both steroids to CBG is sa turable in the therapeutic concentration range. General drug binding e quations were applied to two drugs and two binding sites and two impli cit cubic equations were derived. These equations cannot be solved alg ebraically. However, the free concentration can be calculated using sp readsheet programs on a personal computer. A spreadsheet for these equ ations was developed using EXCEL 5.0 and its SOLVER option. Free conce ntrations of prednisolone and cortisol were determined as a function o f total concentrations of both ligands. The simulations show that the protein binding of cortisol remains relatively constant in the physiol ogical range but changes when exogenous corticosteroid is present. How ever, the degree of protein binding of exogenous corticosteroids that bind to CBG depends on the cortisol concentration which competes for b inding sites. At the same time, the exogenous corticosteroid suppresse s the release of endogenous cortisol. The presented approach is able t o take all of these pharmacokinetic and pharmacodynamic interactions i nto account leading to a more accurate estimation of active free corti costeroid concentrations.