Physiologically Based Pharmacokinetic Modeling: The Reversible Metabolism and Tissue-Specific Partitioning of Methylprednisolone and Methylprednisone in Rats

The pharmacokinetics (PK) of methylprednisolone (MPL) exhibited tissue-specific saturable binding and reversible conversion with its metabolite, methylprednisone (MPN). Blood and 11 tissues were collected in male rats after intravenous (IV) bolus doses of 50 mg/kg MPL and 20 mg/kg MPN and upon IV infusion of MPL and MPN at 0.3, 3, and 10 mg/h/kg. The concentrations of MPL and MPN were simultaneously measured. A comprehensive physiologically based pharmacokinetic (PBPK) model was applied to describe the plasma and tissue profiles and estimate PK parameters of the MPL/MPN interconversion system. Both dosed and formed MPL and MPN were in rapid equilibrium or achieved steady-state rapidly in plasma and tissues. MPL tissue partitioning was nonlinear with highest capacity in liver (322.9 ng/mL), followed by kidney, heart, intestine, skin, spleen, bone, brain, muscle, and lowest in adipose (2.74 ng/mL), and displayed high penetration in lung. The tissue partition coefficient of MPN was linear but widely variable (0.15~5.38) across most tissues with nonlinear binding in liver and kidney. The conversion of MPL to MPN occurred in kidney, lung, and intestine with total clearance of 429 mL/h, and the back conversion occurred in liver and kidney at 1342 mL/h. The irreversible elimination clearance of MPL was 789 mL/h from liver and that of MPN was 2758 mL/h with liver accounting for 44%, lung 35%, and kidney 21%. The reversible metabolism elevated MPL exposure in rats by 13%. This highly complex PBPK model provided unique and comprehensive insights into the disposition of a major corticosteroid. Significance Statement Our dual PBPK study and model of MPL/MPN with multiple complexities reasonably characterized and parameterized their disposition, localized their reversible conversion, rendered advanced appreciation of tissue partitioning, and provided greater insights into the interpretation of their pharmacodynamics in rats. Drug knowledge gained in this study may be translatable to higher-order species to appreciate the clinical utility of MPL. The complex model itself is instructive for advanced PBPK analysis of drugs with reversible metabolism and/or nonlinear tissue partitioning features.