Four-compartment diffusion model of cortisol disposition: Comparison to three alternative models in current clinical use

Abstract

Context Estimated rates of cortisol elimination and appearance vary according to the model used to obtain them. Generalizability of current models of cortisol disposition in healthy humans is limited. Objective Development and validation of a realistic, mechanistic model of cortisol disposition that accounts for the major factors influencing plasma cortisol concentrations in vivo (Model 4), and comparison to previously described models of cortisol disposition in current clinical use (Models 1-3). Methods The four models were independently applied to cortisol concentration data obtained for the hydrocortisone bolus experiment (20 mg) in two clinical groups: healthy volunteers (HV, n = 6) and CBG-deficient (n = 2). Model 4 used Fick’s first law of diffusion to model free cortisol flux between vascular and extravascular compartments. Pharmacokinetic parameter solutions for Models 1-4 were optimized by numerical methods, and model-specific parameter solutions were compared by RM-ANOVA. Models and respective parameter solutions were compared by mathematical and simulation analyses, and an assessment tool was used to compare performance characteristics. Results Cortisol half-lives differed significantly between models (all P < 0.001) with significant model-group interaction (P = 0.02). In comparative analysis, Model 4 solutions yielded significantly reduced free cortisol half-life, improved fit to experimental data (both P < 0.01), and superior model performance. Conclusions The proposed 4-compartment diffusion model (Model 4) is consistent with relevant experimental observations and met the greatest number of empiric validation criteria. Cortisol half-life solutions obtained using Model 4 were generalizable between HV and CBG-deficient groups and bolus and continuous modes of hydrocortisone infusion.

Distribution of Cortisol in Human Plasma in vitro: Equilibrium Solutions for Free Cortisol Using Equations of Mass Conservation and Mass Action

“…In the minimal model, represented by Table 2,theseparametersincludeK 11 and N. In the competition model, represented by 2 Â 2 Table 5, additional parameters, including affinity constant forcompetitor(P)bindingtoCBG[K 21 ], were obtained. Our finding that the competition model provided significantly better fit to experimental data as well as better residual plots compared to the minimal model provide additional support, albeit indirect, for the presence of ligands (P) that compete for CBG-cortisol binding [58]. The identity of the putative ligand(s) (P) remains speculative.…”

“…This transition of parameters of interest from the in vitro equilibrium condition to the in vivo dynamic condition involves dividing association equilibrium constants into cognate on-and off-rate constants. Thus, the in vivo model uses on-and off-rate constants rather equilibrium association constants and differential equations (see [2]) rather than the iterative equilibrium equations discussed herein.…”

“…A minimal model for equilibrium solutions considers a single ligand (cortisol) and its two principal BPs in human plasma, namely CBG and albumin [2,4,7]. Whereas CBGcortisol binding is specific, high-affinity, and saturable, albumin-cortisol binding is nonspecific, low affinity, and non-saturable at physiologic concentrations of plasma cortisol [8].…”

“…Our use of the term is restricted to these concentrations without any intended endorsement of proposed biological activity of albumin-bound cortisol related to capillary transit times [31][32][33][34]. In fact, from a modeling perspective of systemic concentrations of cortisol in vivo,X FA does not diffuse between vascular and extravascular compartments; rather, X FA varies in time-dependent fashion in dynamic equilibrium with X F and X FC (in the plasma compartment) [2,8,35]. Nonetheless, the concept of bioavailable cortisol may be useful to cortisol in vitro, as it parses the problem of estimating free cortisol into two tasks.…”

“…Cortisone binds CBG with intermediate affinity [14], raising the possibility that other metabolites of cortisol might also compete for CBG-cortisol binding. This hypothesis was further explored in an analysis comparing women on oral contraceptive pills (OC) and healthy volunteer (HV) groups based on data of Perogamvros et al [58,59]. The data set was especially useful for modeling cortisol distribution in vitro, since multiple measurements of X TotF ,X F , and free cortisone (X E ) were obtained in the same individual at multiple time points spanning a broad range of cortisol concentrations.…”