Four-compartment diffusion model of cortisol disposition: Comparison to three alternative models in current clinical use
Open accessAbstract
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.
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The reported elimination rate constant for unbound cortisol (53.4 h−1) is well in accordance with our estimated value (49.3 h−1).
“Additionally, the reported elimination rate constant for unbound cortisol (53.4 h− 1) is well in accordance with our estimated value (49.3 h− 1).”
From A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy (2024) · cites this paper as [42]
The distribution of cortisol in the extravascular compartment presented by Dorin et al. is comparably accounted for in our framework by the presence of a peripheral compartment for cortisol.
“This process is comparably accounted for in our framework by the presence of a peripheral compartment for cortisol.”
From A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy (2024) · cites this paper as [42]
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“Lastly, a mechanistic disposition model for cortisol that included distribution of cortisol in the extravascular compartment was presented by Dorin et al. in 2022 [ 42]: This process is comparably accounted for in our framework by the presence of a peripheral compartment for cortisol.”
- Authors
- Dorin, R. I., Urban, F. K., Perogamvros, I., & Qualls, C. R.
- Affiliations
- University of New Mexico (US)
- Florida International University (US)
- University of Manchester (GB)
- Corresponding author
- Dorin, Richard I
- Venue
- Journal of the Endocrine Society
- Publisher
- The Endocrine Society
- Published
- 2022-11-14
- Volume
- 7
- Issue
- 2
- Pages
- bvac173-bvac173
- ISSN
- 2472-1972 (ISSN-L)
- PMC
- PMC9815201
- OpenAlex
- W4308964967
- Cited by
- 4
- References
- 63
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- Locations
- Journal of the Endocrine Society (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- free cortisol, Fick's first law of diffusion, pharmacokinetic modeling, healthy volunteers
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