PHARMACOKINETICS AND TISSUE DISTRIBUTION OF METHOTREXATE AFTER INTRAVENOUS-INJECTION OF DIFFERENTLY CHARGED LIPOSOME-ENTRAPPED METHOTREXATE TO RATS
PHARMACOKINETICS AND TISSUE DISTRIBUTION OF METHOTREXATE AFTER INTRAVENOUS-INJECTION OF DIFFERENTLY CHARGED LIPOSOME-ENTRAPPED METHOTREXATE TO RATS
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DOI：
10.1016/0378-5173(94)90412-x
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发表时间：
1994-07-25
影响因子：
5.8
通讯作者：
LEE, BJ
中科院分区：
文献类型：
--
作者：
KIM, CK;LEE, MK;LEE, BJ
通过对反相蒸发囊泡法（REV）的改进，制备了脂质体包裹的[H-3]MTX。用磷脂酰胆碱（PC）、胆固醇（CH）和α -生育酚（α -t）（摩尔比8:4:1 . 0）的混合物制备中性脂质体。将硬脂胺（SA）（摩尔比8:4:0.1:1）和磷酸二酯（DCP）（摩尔比8:4:0.1:1）分别掺入中性脂质体中制备带正电和负电的脂质体。在大鼠血浆存在的情况下，脂质体[H-3]MTX的释放曲线具有相同的形状，无论表面电荷如何，都表现为最初的快速释放，然后缓慢释放。[H-3]MTX从脂质体中的释放曲线取决于脂质体的表面电荷。与带正电和中性的脂质体相比，带负电的脂质体显示出更大的[H-3]MTX释放。在大鼠血浆存在的情况下，带负电荷的脂质体中[H-3]MTX的体外释放增强可能是由于脂质体的脂质组成与血浆成分的相互作用，导致脂质体膜的不稳定，从而改变了药物通过脂质双层的释放。给大鼠静脉注射游离的和脂粒包裹的[H-3]MTX后，血流中[H-3]MTX的消除呈双相模式，即在30分钟内迅速下降，随后是较慢的消除阶段。与游离的[h -3]MTX相比，脂质体包裹的[h -3]MTX在2小时内保持了更高更长时间的血浆浓度，并且在血浆中以完整的形式存在。脂质体包裹的[h -3]MTX提高了血浆中的生物利用度，这是由于脂质体的脂质双层延缓药物释放和保护药物清除。带负电荷的脂质体包裹的药物被更快地从血液中清除，这是由于肝脏在更大程度上快速摄取，可能是通过网状内皮系统（RES），因为脂质体包裹的药物不能被肾脏（MTX的主要消除器官）消除。脂质体包裹的[H-3]MTX的组织分布与游离的[H-3]MTX有很大的不同。脾脏中中性和带负电荷的脂质体对药物的摄取明显增加。在大鼠静脉注射后2小时，与带正电和中性电的脂质体相比，带负电的脂质体也增加了药物在肝脏、肺和淋巴结的定位。从这些发现来看，含有抗癌药物的脂质体似乎是靶向这些部位的有效载体系统。虽然脂质体包裹的[H-3]MTX在组织中广泛分布，但脂质体表面电荷的确切作用尚不清楚，但显然脂质体表面电荷改变了药物的生物分布和膜渗透。
Liposome-entrapped [H-3]MTX was prepared by modification of reverse-phase evaporation vesicle (REV) methods. Neutral liposomes were prepared with a mixture of phosphatidylcholine (PC), cholesterol (CH) and alpha-tocopherol (alpha-T) (8:4:0.1, molar ratio). Positively and negatively charged liposomes were also prepared by incorporation of stearylamine (SA) (8:4:0.1:1, molar ratio) and dicetyl phosphate (DCP) (8:4:0.1:1, molar ratio) into neutral liposomes, respectively. The release profiles of [H-3]MTX from liposomes in the presence of rat plasma were the same shape regardless of surface charges, showing initial fast release followed by much slower release. The release profiles of [H-3]MTX from liposomes were dependent on the surface charge of liposomes. Negatively charged liposomes showed much greater [H-3]MTX release compared to positively charged and neutral liposomes. The enhanced in vitro release of [H-3]MTX from negatively charged liposomes in the presence of rat plasma may be due to the interaction of incorporated lipid compositions of liposomes with plasma components, resulting in a change in drug release through the lipid bilayers by destabilization of the liposomal membranes. After intravenous (i.v.) injection of free and liposome-entrapped [H-3]MTX to rats, the elimination of [H-3]MTX from the blood stream showed biphasic patterns indicating rapid declining disposition up to 30 min followed by a slower elimination phase. Liposome-entrapped [H-3]MTX maintained a higher and longer plasma concentration, and mainly intact form in plasma compared to free [H-3]MTX for 2 h. Liposome-entrapped [H-3]MTX enhanced bioavailability in plasma due to the retardation of drug release and protection of drug clearance by lipid bilayers of liposomes. Negatively charged liposome-entrapped drug was cleared more rapidly from the blood, resulting from the rapid uptake by liver to a greater extent, possibly via the reticuloendothelial system (RES), since liposome-entrapped drug cannot be eliminated by the kidney, the main eliminating organ for MTX. The tissue distribution of liposome-entrapped [H-3]MTX was widely different when compared to free [H-3]MTX. There was a markedly increased uptake of drug in spleen from neutral and negatively charged liposomes. Negatively charged liposomes also increased localization of drug in liver, lung and lymph nodes compared to neutral and positively charged liposomes at 2 h after i.v. injection to rats. From these findings, liposomes containing anticancer drugs would appear to be an effective carrier system for targeting to these sites. Although liposome-entrapped [H-3]MTX was widely distributed in tissues without the exact role of the liposomal surface charge being known, it was evident that the surface charge of liposomes altered the biodistribution and membrane permeation of drug.