Mishina E V, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260, USA.
Pharm Res. 1996 Jan;13(1):141-5. doi: 10.1023/a:1016054022750.
Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the immune system and enhances immunosuppressive activity of the steroid. We performed dose-dependent and chronic dose studies of L-MPL versus MPL.
Male Lewis rats received 10 mg/kg i.v. bolus doses of L-MPL (Solu-Medrol). Plasma samples were obtained over an 8 day period and MPL concentrations were assayed by HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte proliferation induced with PHA.
Drug concentrations declined in a similar manner over the first few hours following MPL or L-MPL. Free MPL was cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistence over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L-MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day 8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg i.v. doses of L-MPL versus MPL twice a week produce plasma drug profiles similar to those obtained after single doses, indicating that neither free nor liposomal steroid accumulates in tissues. Liposomes without drug simultaneously administered with MPL caused partial prolongation of plasma steroid half-life (8.4 hr).
These studies clarify factors causing prolonged drug persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular pharmacokinetics, and secondary effects of the liposomes are complicating factors in use of L-MPL.
脂质体包裹的甲泼尼龙（L-MPL）靶向免疫系统并增强类固醇的免疫抑制活性。我们对L-MPL与甲泼尼龙（MPL）进行了剂量依赖性和慢性剂量研究。
雄性Lewis大鼠静脉注射10mg/kg的L-MPL（甲强龙）推注剂量。在8天的时间内采集血浆样本，并通过高效液相色谱法测定MPL浓度。免疫抑制作用通过抑制PHA诱导的体外脾细胞增殖来测量。
在MPL或L-MPL给药后的最初几个小时内，药物浓度以相似的方式下降。游离MPL在6小时内从血浆中清除，而相同剂量的L-MPL在8天内持续存在。游离和脂质体药物的药代动力学参数均观察到剂量依赖性变化。剂量从2mg/kg增加到10mg/kg导致清除率从5.9增加到10.5（MPL），从1.8增加到2.3L/hr/kg（L-MPL）。L-MPL在5天内抑制了细胞增殖，在第8天恢复到基线水平；游离MPL仅在10小时内产生免疫抑制作用。每周两次静脉注射2mg/kg的L-MPL与MPL产生的血浆药物谱与单次给药后获得的相似，表明游离或脂质体类固醇均未在组织中蓄积。与MPL同时给药的无药物脂质体导致血浆类固醇半衰期部分延长（8.4小时）。
这些研究阐明了导致L-MPL药物持久性延长和免疫抑制的因素。非线性处置、不规则的药代动力学以及脂质体的次要作用是使用L-MPL的复杂因素。
