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

Abstract

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