TY - JOUR T1 - Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics - I: Determination and Prediction of Dexamethasone and Methylprednisolone Tissue Binding in the Rat JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.257519 SP - jpet.119.257519 AU - Vivaswath S. Ayyar AU - Dawei Song AU - Debra C. DuBois AU - Richard R. Almon AU - William J. Jusko Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/06/13/jpet.119.257519.abstract N2 - The plasma and tissue binding properties of two corticosteroids, dexamethasone (DEX) and methylprednisolone (MPL), were assessed in the rat in anticipation of developing PBPK and PK/PD models. The tissue-to-plasma partition coefficients (KP) of DEX and MPL was determined in liver, muscle, and lung in vivo following steady-state infusion and bolus injection in rats. Since KP is often governed by reversible binding to macromolecules in blood and tissue, an attempt was made to assess KP values of DEX and MPL by in vitro binding studies using rat tissue homogenates and to compare these estimates to those obtained from in vivo kinetics after dosing. The KP of both steroids were also predicted in rat tissues using mechanistic tissue composition-based equations and compared. The plasma binding of DEX and MPL was linear with moderate binding (60.5 and 82.5%) in male and female rats. In vivo estimates of steroid uptake appeared linear across the tested concentrations and KP was highest in liver and lowest in muscle for both steroids. Assessment of hepatic binding of MPL in vitro was severely affected by drug loss at 37°C in male liver homogenates, whereas DEX was stable in both male and female liver homogenates. With the exception of MPL in liver, in vitro-derived KP estimates reasonably agreed with in vivo values. The mechanistic equations modestly under-predicted KP for both drugs. Tissue metabolism, saturable tissue binding, and active uptake are possible factors which can complicate assessments of in vivo tissue binding of steroids when using tissue homogenates.SIGNIFICANCE STATEMENT Assuming the free hormone hypothesis, the ratio of the unbound drug fraction in plasma (fu,p) and in tissues (fu,t) defines the tissue-to-plasma partition coefficient (KP), an important parameter in physiologically-based pharmacokinetic (PBPK) modeling that determines total drug concentrations within tissues and the steady-state volume of distribution. This study assessed the plasma and tissue binding properties of the synthetic corticosteroids, dexamethasone and methylprednisolone in rats using ultrafiltration and tissue homogenate techniques. In vitro-in vivo and in silico-in vivo extrapolation of KP was assessed for both drugs in liver, muscle, and lung. Although fairly successful across the tissues, in vitro homogenate studies severely under-predicted the KP of methylprednisolone in liver, partly attributable to the extensive hepatic metabolism. ER -