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

Abstract

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.