Haughey D B, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
J Pharm Sci. 1992 Feb;81(2):117-21. doi: 10.1002/jps.2600810203.
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 approximately 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 (Vdss) and central volume of distribution (Vdc), 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 (Vmax) and affinity (Km) 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.
口服甲基泼尼松龙游离醇及静脉注射甲基泼尼松龙琥珀酸钠后，测定了低剂量（10mg/kg）和高剂量（50mg/kg）甲基泼尼松龙的生物利用度。通过高效液相色谱法测定血浆中甲基泼尼松龙和甲基泼尼松（可逆代谢物）的浓度。静脉注射后甲基泼尼松龙的全身利用率（F）为49 - 57%，口服后约为35%。聚乙二醇与乙醇对类固醇的增溶作用对其处置无影响。甲基泼尼松龙的表观全身清除率（CL）为21 mL/min（低剂量），约为肝血流量的两倍。观察到稳态分布容积（Vdss）和中央分布容积（Vdc）、容积及表观CL随剂量的依赖性变化。由于甲基泼尼松形成清除率（CL12）饱和，甲基泼尼松龙与甲基泼尼松的AUC比值随剂量降低，但这是一条次要的代谢途径。平均驻留时间（MRT）随剂量增加三倍。米氏容量（Vmax）和亲和力（Km）常数的图形估计值与低剂量实验数据的CL值合理一致。静脉注射甲基泼尼松龙琥珀酸钠的全身利用率低部分归因于所形成的甲基泼尼松龙的连续首过肝代谢。由于广泛的首过效应、非线性消除、非线性分布及可逆代谢，甲基泼尼松龙在大鼠体内的处置较为复杂。
