Kinetics of cortisol and cortisone binding to corticosteroid binding globulin and albumin <i>in vivo</i>

estimates. This work provides a quantitative framework for predicting unbound cortisol and cortisone across physiological and disease states by accounting for both changes in ligand and protein concentrations. This enables extrapolation without reparameterization and supports exploration of conditions such as pregnancy, adrenal insufficiency, and liver disease, informing interpretation of altered cortisol concentrations in these populations. Significance statement: cortisol and cortisone binding. The developed model was applied to predict unbound cortisol and cortisone concentrations in physiological and pathophysiological states and can be integrated into pharmacokinetic models. Our analysis demonstrates that cortisol and cortisone binding affinities estimated in the native plasma environment differ from those measured using purified proteins. These differences have important implications for predicting and analyzing unbound cortisol concentrations.