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 (i.v.) bolus doses of 50 mg/kg MPL and 20 mg/kg MPN and upon i.v. infusion of MPL and MPN at 0.3, 3, and 10 mg/h per 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 displaying 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.