Huong T M, Ishida T, Harashima H, Kiwada H
Department of Pharmacokinetics and Pharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1, Shomachi, 770-8505, Tokushima, Japan.
Int J Pharm. 2001 Mar 14;215(1-2):197-205. doi: 10.1016/s0378-5173(00)00691-8.
In this study, we investigated the contribution of the complement system to the biodistribution of phosphatidylserine (PS)-containing liposomes in rat and guinea pig. It appeared that the inclusion of PS in the liposome formulation accelerates the rate of liposome uptake by liver, resulting in rapid elimination of the liposomes from blood circulation. Pretreatment with K76COOH (K76), an anti-complement agent, decreased the rapid uptake of PS-containing liposomes by guinea pig liver, resulting in increasing blood concentration of the liposomes. Significant complement-dependent liposome destabilization was observed in vitro in both animals, whereas the complement-dependent destabilization in vivo was likely only a part of the process of the clearance of the PS-containing liposomes. This discrepancy suggests that the rate of complement-dependent liposome uptake by liver is much faster than the rate of complement-dependent liposome destabilization in vivo. Pretreatment of K76 dramatically inhibited the binding of C3 fragments, one of dominant opsonins, to PS-containing liposomes in guinea pig under both in vivo and in vitro conditions. This finding suggests that the C3 fragments in the system are responsible for the clearance of the PS-containing liposomes in guinea pig. In rat, in contrast to guinea pig, in vivo binding of C3 fragments was not inhibited by K76-pretreatment, while in vitro binding was inhibited. This discrepancy may be due to different experimental conditions between in vitro and in vivo assay. Nevertheless, based on the observations in this study, the complement components are most likely involved in the clearance of the PS-containing liposomes in rat. Taken together, the activity of PS in enhancing the liposome clearance appears to be mediated by the complement components, presumably C3 fragments, in both guinea pig and rat. This is a first report showing the mechanism on the hepatic uptake of the PS-containing liposomes in guinea pig.
在本研究中，我们调查了补体系统对含磷脂酰丝氨酸（PS）脂质体在大鼠和豚鼠体内生物分布的影响。结果显示，脂质体制剂中加入PS可加速肝脏对脂质体的摄取速率，导致脂质体从血液循环中快速清除。用抗补体剂K76COOH（K76）预处理可降低豚鼠肝脏对含PS脂质体的快速摄取，从而使脂质体的血药浓度升高。在两种动物的体外实验中均观察到明显的补体依赖性脂质体去稳定化现象，而体内补体依赖性去稳定化可能只是含PS脂质体清除过程的一部分。这种差异表明，肝脏对补体依赖性脂质体的摄取速率比体内补体依赖性脂质体去稳定化速率快得多。在体内和体外条件下，K76预处理均显著抑制了豚鼠体内主要调理素之一C3片段与含PS脂质体的结合。这一发现表明，该系统中的C3片段负责豚鼠体内含PS脂质体的清除。与豚鼠不同，在大鼠中，K76预处理并未抑制C3片段的体内结合，而体外结合则受到抑制。这种差异可能是由于体外和体内实验条件不同所致。尽管如此，基于本研究的观察结果，补体成分很可能参与了大鼠体内含PS脂质体的清除。综上所述，PS增强脂质体清除的活性似乎是由豚鼠和大鼠体内的补体成分（可能是C3片段）介导的。这是首次报道豚鼠肝脏摄取含PS脂质体的机制。
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