Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo
Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo
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细胞色素 P450 的诱导参与聚乙二醇化脂质体在体内诱导的加速血液清除现象
DOI：
10.1124/dmd.118.085340
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发表时间：
2019-04-01
影响因子：
3.9
通讯作者：
Chen，Weidong
中科院分区：
文献类型：
--
作者：
Wang，Fengling;Wu，Yifan;Chen，Weidong
聚乙二醇（PEG）被认为是一种有吸引力的赋形剂来修饰脂质体，由于其延长循环的性质。然而，静脉注射聚乙二醇包被脂质体（PEG-L）通常会触发随后剂量从血液循环中迅速全身清除，这被称为加速血液清除（ABC）现象。因此，由于细胞色素P450 （P450）活性的诱导可能导致药物清除增强，这促使我们研究P450参与ABC现象的可能性。本研究制备了聚乙二醇包被多西紫杉醇脂质体，并利用聚乙二醇修饰脂质体对大鼠反复注射后ABC现象的影响程度进行了评价。值得注意的是，两次给药的时间间隔为1 ~ 7 d时，出现了ABC现象，其幅度在第3天达到最大值，然后逐渐减少时间。同时，每隔3天重复注射PEG-L可检测到雄性大鼠体内CYP3A1、CYP2C6和CYP1A2的活性升高。重复注射组肝脏CYP3A1、CYP2C6、CYP1A2的表达水平也显著升高，且间隔3 d组表达水平最高。P450选择性抑制剂证实对肝脏CYP3A1的抑制伴随着ABC现象的减弱，这强烈表明P450可能是通过重复注射PEG-L诱导的，从而有利于第二次剂量的代谢清除。综上所述，我们首次证明了p450在ABC现象中的作用不容忽视。
Polyethylene glycol (PEG) is recognized as an attractive excipient to modify liposomes due to its extended-circulation properties. Nevertheless, intravenous injection of polyethylene glycol-coated liposomes (PEG-L) usually triggers a rapid systemic clearance of the subsequent dose from blood circulation, which is referred to as an accelerated blood clearance (ABC) phenomenon. Therefore, since the induction of cytochrome P450 (P450) activity may lead to enhanced drug clearance, it motivated us to investigate the possibility of P450 involvement in the ABC phenomenon. In this study, polyethylene glycol-coated liposomal docetaxel was prepared and used to evaluate the magnitude of the ABC phenomenon in rats induced by repeated injection of PEG-modified liposomes. Notably, the ABC phenomenon was observed when the time interval between two doses was from 1 to 7 days, and its magnitude reached the maximum level at 3 days before gradually decreasing the time. Meanwhile, increased activity of CYP3A1, CYP2C6, and CYP1A2 was detected when PEG-L was repeatedly injected in male rats at a 3-day interval. Consistently, the expression levels of hepatic CYP3A1, CYP2C6, and CYP1A2 were also significantly increased in the repeated injection groups and their levels were highest in the 3-day interval group. P450 selective inhibitors confirmed the inhibition of hepatic CYP3A1 was accompanied by an attenuated magnitude of the ABC phenomenon, which strongly suggests that P450s may be induced by repeated injection of PEG-L, thus favoring metabolic clearance of the second dose. Collectively, herein, for the first time we demonstrate that the contribution of P450s should not be ignored in the ABC phenomenon.