In vitro effect of mPEG2k-PCLx micelles on rat liver cytochrome P450 enzymes

The present study was aimed to evaluate the effects of amphiphilic copolymer micelles on six major hepatic cytochrome P450 (CYP) isoforms. A series of mPEG 2k -PCL x polymeric micelles (mPEG 2k -PCL 2k , mPEG 2k -PCL 3.5k , mPEG 2k -PCL 5k and mPEG 2k -PCL 10k ) ranging from 20 to 100  nm were prepared to investigate the inhibitory or inductive activities by in vitro incubations of rat liver microsomes and primary rat hepatocytes. Inhibition of these polymeric micelles on CYP1A2 , CYP2B1 , CYP2C6, CYP2C11 , CYP2D2 and CYP3A1/2 isoenzymes were observed above their critical micelle concentrations (>10 μg·mL −1 ) and in a concentration-dependent manner. The mPEG 2k -PCL 2k micelles showed the strongest inhibition of CYP1A2, followed by CYP2C11. The micelles with lower molecular weight PCL segment exhibited more potent inhibitory potential. Induction on CYP1A2, CYP2B1 and CYP3A1/2 activity (2.1–7.2-fold, 1.5–2.4-fold and 1.3–3.0-fold, respectively) were detected at all tested concentrations (0.1–1000 μg·mL −1 or 0.1–100 μg·mL −1 ). Accordingly, most of the mRNA levels were upregulated. As demonstrated in ex vivo fluorescence imaging results, the mPEG 2k -PCL x micelles mainly accumulated in the liver after intravenous administration. In conclusion, mPEG 2k -PCL x micelles can interfere with the normal metabolic function of CYP450s in vitro , indicating polymeric micelles as promising drug nano-carriers might cause micelle–drug interaction and the in vivo interaction deserves further investigation.