In vitroeffect of mPEG2k-PCLxmicelles on rat liver cytochrome P450 enzymes

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Abstract

The present study was aimed to evaluate the effects of amphiphilic copolymer micelles on six major hepatic cytochrome P450 (CYP) isoforms. A series of mPEG2k-PCLx polymeric micelles (mPEG2k-PCL2k, mPEG2k-PCL3.5k, mPEG2k-PCL5k and mPEG2k-PCL10k) ranging from 20 to 100nm 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 (>10μg·mL−1) and in a concentration-dependent manner. The mPEG2k-PCL2k 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 (0.1–1000μg·mL−1 or 0.1–100μg·mL−1). Accordingly, most of the mRNA levels were upregulated. As demonstrated in ex vivo fluorescence imaging results, the mPEG2k-PCLx micelles mainly accumulated in the liver after intravenous administration. In conclusion, mPEG2k-PCLx 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.

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