The sub-chronic impact of mPEG2k-PCLx polymeric nanocarriers on cytochrome P450 enzymes after intravenous administration in rats

Abstract Recent studies indicated obvious impacts of nano-carriers on cytochrome P450 enzymes (CYP450s) in vitro , but the effects in vivo are still unknown. In the present research, mPEG 2k -PCL x micelles with different length of hydrophobic block (2000∼10000 Da) were intravenously administrated into rats for 14 days to evaluate the sub-chronic influences in the metabolic function of hepatic CYP450s. Although CYP1A1/B2 was susceptible to mPEG 2k -PCL x micelles compared with other CYP isoenzymes, induction was mainly observed and varied with micelle type, administration dose, and CYP isoform. Interestingly, mPEG 2k -PCL 3.5k micelles at 5 mg/kg increased the activity of CYP1A2, CYP2B1, CYP2C6, CYP2C11, and CYP3A1/2 while mPEG 2k -PCL 5k micelles only induced the latter three enzymes at 75 mg/kg. The mRNA expression of corresponding CYPs was mostly up-regulated by mPEG 2k -PCL 3.5k micelles whilst less effect in protein level except for CYP3A1/2. Moreover, mPEG 2k -PCL 3.5k micelles could affect the pharmacokinetic properties of phenacetin (CYP1A2), tolbutamide (CYP2C6), omeprazole (CYP2C11), and midazolam (CYP3A1/2) with a decrease of 24.4% in C max , 23.7% in C max , 46.1% in AUC 0-t , and 66.9% in C max at 5 mg/kg, respectively ( P P