Amselem S, Cohen R, Barenholz Y
Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Chem Phys Lipids. 1993 Sep;64(1-3):219-37. doi: 10.1016/0009-3084(93)90067-d.
Design of liposome-based formulations for clinical use can be assisted by employing in vitro assays to predict pharmacokinetics and bioavailability of the drug before employing costly and time-consuming in vivo studies. For such formulations of the anti-cancer drug doxorubicin (DXR) we developed two assays. (A) An assay which determines the dilution-induced DXR release in buffers and plasma. This assay was employed to evaluate two liposomal DXR formulations: (i) membrane-associated liposomal doxorubicin (L-DXR), and (ii) sterically-stabilized liposomes which encapsulate DXR in the aqueous phase of the liposomes (S-DXR). The agreement between the dilution-induced release assay in vitro and the pharmacokinetics of DXR administrated either as L-DXR or as S-DXR in humans suggests that the dilution release assay can be used as a predictor for the pharmacokinetic performance of liposomal formulations. (B) An assay which determines intracellular drug release induced by liposome degradation in the presence of mouse liver lysosome lysate. This assay was used to assess bioavailability of DXR when delivered via L-DXR, which are taken up by the reticuloendothelial system (RES). (C) An assay which complements conventional chromatographic analyses (HPLC or TLC) of the drug, in which a DXR adduct or aggregate was determined by using Sephadex LH-20 gel exclusion chromatography.
在进行代价高昂且耗时的体内研究之前，可通过体外试验来预测药物的药代动力学和生物利用度，以此辅助临床用脂质体制剂的设计。对于抗癌药物阿霉素（DXR）的此类制剂，我们开发了两种试验方法。（A）一种测定缓冲液和血浆中稀释诱导的DXR释放的试验。该试验用于评估两种脂质体DXR制剂：（i）膜相关脂质体阿霉素（L-DXR），以及（ii）在脂质体水相中包裹DXR的空间稳定脂质体（S-DXR）。体外稀释诱导释放试验与L-DXR或S-DXR形式给药的DXR在人体中的药代动力学之间的一致性表明，稀释释放试验可作为脂质体制剂药代动力学性能的预测指标。（B）一种测定在小鼠肝溶酶体裂解物存在下脂质体降解诱导的细胞内药物释放的试验。该试验用于评估通过L-DXR递送时DXR的生物利用度，L-DXR会被网状内皮系统（RES）摄取。（C）一种补充药物常规色谱分析（HPLC或TLC）的试验，其中使用葡聚糖LH-20凝胶排阻色谱法测定DXR加合物或聚集体。
