Physiologically based pharmacokinetic modeling the reversible metabolism and tissue-specific partitioning of methylprednisolone and methylprednisone in rats
Authors: Yu Ruihong , Jusko William 
Published: February 2025

Objectives: Numerous drugs form metabolites that revert back to the parent compound. Methylprednisolone (MPL) is a frequently used corticosteroid for treatment of acute respiratory distress syndrome, such as COVID-19, and other conditions [1]. The pharmacologically active MPL exhibits reversible conversion to inactive methylprednisone (MPN) in both man and various animal species [2]. Such interconversion mediated by tissue-specific 11β-hydroxysteroid dehydrogenases [3] together with some potential non-linear dispositions complicates MPL pharmacokinetic (PK) analysis and interpretation. This study assesses the PK of MPL after dosing rats with either the parent or the metabolite compound.Methods: 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 with 29 compartments was applied to describe the plasma and tissue profiles and estimated 39 PK parameters of the MPL/MPN interconversion system. Results: 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%. Conclusions: This 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.Citations: [1] Meduri GU, Annane D, Confalonieri M, Chrousos GP, Rochwerg B, Busby A, Ruaro B, Meibohm B (2020) Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med 46:2284-2296.[2] Ebling WF, Jusko WJ (1986) The determination of essential clearance, volume, and residence time parameters of recirculating metabolic systems: the reversible metabolism of methylprednisolone and methylprednisone in rabbits. J Pharmacokinet Biopharm 14:557-599.[3] Chapman K, Holmes M, Seckl J (2013) 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev 93:1139-1206.