ORF25-02 - Pharmacokinetics of Salivary Dexamethasone and Its Downstream Impact on Salivary Cortisol and Cortisone: A Cross-Sectional Study.

Context
The dexamethasone suppression test (DST) is central to the evaluation of hypercortisolism, yet inter-individual variability in dexamethasone absorption and clearance may confound interpretation, and real-world pharmacokinetic data are limited.

Objectives
To quantify dexamethasone exposure using serial salivary measurements during DST, characterize variability in dexamethasone absorption and clearance and its relationship with salivary cortisol/cortisone dynamics, identify clinical and biochemical factors associated with dexamethasone exposure.

Methods
We conducted a cross-sectional study, August -December 2025, of adults undergoing DST. Saliva samples were collected at five time points over 60 hours following oral dexamethasone administration, starting with the morning following the overnight dexamethasone administration. Liquid chromatography-tandem mass spectrometry was used to measure salivary cortisol, cortisone, and dexamethasone.

Outcomes: Salivary dexamethasone concentrations over time, time to undetectable dexamethasone ( < 5 ng/dL), factors associated with time to undetectable dexamethasone, cortisone diurnal recovery.

Results
In 60 participants undergoing the 1mg DST (median age 59.8 years, 78% women), median salivary dexamethasone concentrations declined from 72 ng/dL (IQR 45–117 ng/dL) at 9 hours (day 1 morning) to 6 ng/dL (0–13 ng/dL) at 23 hours, 5 ng/dL (0-11 ng/dL) at 32 hours, and 0 ng/dL (0-0 ng/dL) at 47 and 56 hours, with 91% of participants reaching undetectable concentrations by 56 hours.
Median salivary cortisone was 64.5 ng/dL (50.0-110.5 ng/dL) on the morning of day 1, 398.5 ng/dL (99.6-841.8 ng/dL) on the morning of day 2, and 831.3 ng/dL (592.2-1241.6 ng/dL) on the morning of day 3 post-dexamethasone administration.

Dexamethasone concentrations and clearance time did not differ by post-DST serum cortisol ( < 1.8 vs ≥1.8 µg/dL). In univariable analyses, oral estrogen use was associated with faster clearance (HR 5.08, P=0.005), while older age was associated with prolonged exposure (HR per 10-year increase 0.75, P=0.007). In multivariable models, older age remained independently associated with longer time to undetectable dexamethasone (HR 0.72, P=0.045). No associations with dexamethasone clearance were observed with Glucagon-like peptide-1 (GLP-1) agonist, Cytochrome P450 3A4 (CYP3A4) inducer or inhibitor use.

Conclusion
Older age is associated with prolonged dexamethasone exposure, while oral estrogen use accelerates clearance. Residual dexamethasone commonly persists up to 48 hours after 1-mg DST, with cortisone recovery peaking by the third morning. These findings support delaying baseline cortisol or cortisone assessment until day 3 post-DST, when dexamethasone is undetectable in most patients, and physiological diurnal patterns are restored.