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Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo

文献类型：期刊论文

作者Wang, Fengling1,2; Wu, Yifan1; Zhang, Jiwen3; Wang, Huihui1; Xie, Xiaoting1; Ye, Xi1,2; Peng, Daiyin1; Chen, Weidong1
刊名DRUG METABOLISM AND DISPOSITION
出版日期2019-04-01
卷号47期号:4页码:364-376
ISSN号0090-9556
DOI10.1124/dmd.118.085340
通讯作者Peng, Daiyin(pengdy@ahtcm.edu.cn) ; Chen, Weidong(wdchen@ahtcm.edu.cn)
英文摘要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.
WOS关键词SOLID LIPID NANOPARTICLES ; REPEATED INJECTIONS ; DELIVERY-SYSTEMS ; DRUG-METABOLISM ; PROTEIN CORONA ; ABC PHENOMENON ; CHAIN-LENGTH ; VITRO ; INHIBITION ; PHARMACOKINETICS
资助项目National Natural Science Foundation of China[81773988] ; Natural Science Foundation of Anhui University of Chinese Medicine[2018zrzd04]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000462570400003
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
源URL[http://119.78.100.183/handle/2S10ELR8/290166]  
专题中国科学院上海药物研究所
通讯作者Peng, Daiyin; Chen, Weidong
作者单位1.Anhui Univ Chinese Med, Sch Pharmaceut Sci, Inst Drug Metab, Hefei, Anhui, Peoples R China
2.Second Peoples Hosp Hefei, Dept Pharm, Hefei, Anhui, Peoples R China
3.Chinese Acad Sci, Ctr Drug Delivery Syst, Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Fengling,Wu, Yifan,Zhang, Jiwen,et al. Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo[J]. DRUG METABOLISM AND DISPOSITION,2019,47(4):364-376.
APA Wang, Fengling.,Wu, Yifan.,Zhang, Jiwen.,Wang, Huihui.,Xie, Xiaoting.,...&Chen, Weidong.(2019).Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo.DRUG METABOLISM AND DISPOSITION,47(4),364-376.
MLA Wang, Fengling,et al."Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo".DRUG METABOLISM AND DISPOSITION 47.4(2019):364-376.

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来源：上海药物研究所

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