Physiologically based pharmacokinetics of dexamethasone in rats featuring nonlinear tissue binding.

Abstract

Dexamethasone (DEX) is a synthetic glucocorticoid used to manage severe inflammatory conditions, including cytokine release syndrome and autoimmune diseases. Although DEX pharmacokinetics (PK) have been characterized in healthy and inflamed rats, tissue distribution under inflammatory conditions and extended exposure were not assessed. This study characterizes the PK of DEX in lipopolysaccharide-challenged rats and updates a previously published physiologically based PK (PBPK) model. Male Wistar rats received subcutaneous DEX at 0.005, 0.025, 0.225, or 2.25 mg/kg doses, followed by 5.0 mg/kg lipopolysaccharide administered intraperitoneally to induce cytokine release syndrome. Plasma, heart, and lung tissues were collected over 48 hours for DEX, and the PK data were integrated with our previous data to refine the PBPK model. Extended sampling revealed a polyexponential decline in plasma and tissues, including a prolonged terminal phase that was not previously captured. The new PBPK model with nonlinear tissue partitioning reflects tissue-specific target-mediated drug disposition. The updated PBPK model accounts for a wide range of DEX doses and reveals prolonged tissue persistence that also appears relevant for several other species. SIGNIFICANCE STATEMENT: The updated physiologically based pharmacokinetic model characterizes dexamethasone (DEX) pharmacokinetics in healthy and lipopolysaccharide-challenged rats, capturing a long terminal phase in plasma and tissues. Incorporating a range of doses, extended sampling times, and tissue-specific nonlinear partitioning, the target-mediated drug disposition model can be used to predict DEX exposure in target organs. These findings enhance the understanding of DEX pharmacokinetics under healthy and inflammatory conditions and provide translational expectations across species.