Bioavailability and nonlinear disposition of methylprednisolone and methylprednisone in the rat

Bioavailability of low (10 mg/kg) and high (50 mg/kg) doses of methylprednisolone was determined after oral administration of the free alcohol of methylprednisolone and iv administration of methylprednisolone sodium succinate. Plasma concentrations of methylprednisolone and methylprednisone (reversible metabolite) were measured by HPLC. Methylprednisolone systemic availability (F) was 49–57% after iv administration and −35% after oral administration. Solubilization of steroids with PEG:ethanol had no effect on their disposition. Apparent systemic clearance (CL) of methylprednisolone was 21 mL/min (low dose), approximately twice the liver blood flow. Dose‐dependent changes in steady‐state volume of distribution (Vd_ss) and central volume of distribution (Vd_c), volumes, and apparent CL were observed. The methylprednisolone‐to‐methylprednisone AUC ratio decreased with dose due to saturation of methylprednisone formation clearance (CL₁₂), but this is a minor metabolic pathway. The mean residence time (MRT) increased threefold with dose. Graphical estimates of the Michaelis‐Menten capacity(V_max) and affinity (K_m) constants were in reasonable agreement with CL values for the low‐dose experimental data. Low systemic availability of iv methylprednisolone sodium succinate was in part due to sequential first‐pass hepatic metabolism of the methylprednisolone formed. Methylprednisolone disposition is complex in the rat due to extensive first‐pass effects, nonlinear elimination, nonlinear distribution, and reversible metabolism.