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| Pharmacokinetic study of genistein -loaded methoxy-terminated polyethylene glycol-lactic acid glycolic acid copolymer micelles after multiple dosing in rats |
| HE Li1 HAN Ruiwei1 YAN Xueying2 |
1.Laboratory for Medicinal Resources and Utilization in Northwest Sichuan, Sichuan University of Traditional Chinese Medicine, Sichuan Province, Mianyang 621000, China;
2.College of Pharmacy，Heilongjiang University of Traditional Chinese Medicine, Heilongjiang Province, Harbin 150040, China |
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Abstract Objective To discuss the pharmacokinetic behavior of genistein (GEN) methoxy-terminated polyethylene glycol-lactic acid glycolic acid copolymer (MePEG-PLGA) micelles administered multiple times in healthy rats. Methods Twenty-four healthy Wistar rats were randomly divided into four groups according to their body weight, with 6 rats in each group, namely the GEN emulsion group and the GEN micelle low, medium and high dose groups. In each group, GEN emulsion and GEN micelles were injected into the tail vein several times, respectively, with the emulsion dose of 40 mg/kg and the micelle dose of 20, 40 and 60 mg/kg. The high performance liquid chromatography (HPLC) was used to analysis drug delivery in different time points after plasma GEN concentration. Results The differences in minimum blood drug concentration (Cmin), half-life (t1/2), area under the curve (AUC0-t), clearance rate (CL) and fluctuation coefficient (DF) between GEN emulsion group and GEN micelles group were statistically significant (P ＜ 0.01). There were no statistically significant differences in the major pharmacokinetic parameters Tmax, t1/2, CL, apparent distribution volume (Vd) and DF in the GEN micelles groups with low, medium and high doses (P ＞ 0.05). Compared with the low-dose group of GEN micelles, the maximum blood concentration (Cmax) and AUC0-t in the medium-dose group of GEN micelles were increased, while the Cmax and AUC0-t in the high-dose group of GEN micelles were increased compared with the low-dose and medium-dose group of GEN micelles, and the differences were highly statistically significant (all P ＜ 0.01). The differences of AUC0-t, AUC0-∞, Cmax and average steady stateconcentration (Cav) in each dose group of GEN micelles increased with the increase of the dose (P ＜ 0.01), and there was a linear relationship between AUC0-t, AUC0-∞, Cmax and Cav and the dose (r > 0.97). There were no significant differences in the major pharmacokinetic parameters Cmax, t1/2, AUC0-t, CL, Vd, MRT0-t between single and multiple doses at the same dose (P ＞ 0.05). Conclusion GEN micelles can significantly delay the retention time of GEN in rats and improve the bioavailability. Moreover, there is a linear relationship between blood drug concentration and dose, and there is no accumulation in rats after repeated drug administration.
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