Background:
Radix Wikstroemia indica is a traditional Chinese medicine (TCM) used as anti-inflammatory and anti-tumor drug. However, it has serious hepatotoxicity, "Sweat soaking method" processed could effectively decrease its hepatotoxicity.
Objective:
The objective of this study is to study the effects of Radix Wikstroemia indica on six kinds of cytochrome P450(CYP450) isozymes of rat liver microsomes before and after processing, and to study the mechanism of Radix Wikstroemia indica processed by the "Sweat soaking method" to reduce liver toxicity in rats.
Methods:
In this study, the effects of Radix Wikstroemia indica and processed Radix Wikstroemia indica on the six main CYP450 isoforms (2E1, 1A2, 2C6, 2D1, 2C11, and 3A1) were investigated in vitro. Using a cocktail probe of CYP450 isoform-specific substrates and their metabolites, we carried out in vitro enzymatic studies in liver microsomal incubation systems via UPLC-MS/MS.
Results:
The results showed that the established UPLC-MS/MS method was precise and reliable. Compared with the blank group, the activities of six enzymes in the RWI and PRWI groups were higher than those in the blank group. At the same dose, the enzyme activities of CYP2E1, CYP1A2, CYP2C6, CYP2C11, and CYP3A1 increased with the increase in dose, and the enzyme activities of the RWI group were higher than those of the PRWI group. The enzyme activities of CYP2E1 and CYP1A2 in the Radix Wikstroemia indica group were significantly increased compared with the blank group, CYP3A1 in the RWI high-dose group was higher than that in the blank group and PRWI group with statistical differences p< or p<.
Conclusion:
The processed Radix Wikstroemia indica could reduce liver injury, and its detoxication mechanism might be related to the decrease in enzyme activity of CYP1A2, CYP2E1 and CYP3A1.
Background:
Daphnoretin, as a known bicoumarin compound that contained various pharmacological activities, was isolated from Wikstroemia indica C.A. Mey (RWI).
Objective:
The study aims to investigate the pharmacokinetic characteristics of daphnoretin from RWI ethanol extracts in rat plasma and to determine daphnetin in rat plasma and various tissues by a rapid, reliable and sensitive ultra high performance liquid chromatography with tandem mass spectrometry method.
Methods:
The UPLC-MS/MS method was established. Daphnoretin and IS (buspirone) were chromatographed on an agilent Zorbax XDB-C18 column (2.1 mm × 50 mm, 3.5 μm), and Gradient elution of acetonitrile-0.15% formic acid in aqueous solution.
Quantification was performed using electrospray ionization in positive ion multiple reaction monitoring mode of the transitions m/z 353.1→179.1 for daphnoretin and m/z 386.3→122.3 for IS.
Results:
Good linearity between 5–10000 ng/mL for cyperidin in plasma and tissue samples (r ≥ 0.99) was resulted. The accuracies of plasma and tissue homogenates ranged from –3.31% to 9.00%, and the precision was less than 5.78%. After that, the validated method was successfully applied to the pharmacokinetics and tissue distribution study of daphnoretin after oral administration of ethanol extract from the roots of RWI to rats.
Conclusion:
Daphnoretin was well absorbed in the systemic circulation after oral administration and was widely distributed in tissues, with the highest concentration in lung tissue. This study is beneficial to the development and utilization of RWI and provides a reasonable reference for its clinical administration.
other:
none
Daphnoretin (DAP), isolated from a traditional Chinese medicine Wikstroemia indica (Linn. C. A. Meyer), could induce apoptosis of hepatocellular cancer (HCC) and inhibit tumor growth. However, the application of DAP in cancer therapies was hampered because to its poor solubility. Herein, this study aimed to design an approach of double-targeted nano-preparation to enable the delivery of DAP to potentiate the therapeutical efficacy in liver cancer via glycyrrhetinic acid-polyethylene glycol-block-poly (D,L-lactic acid)/polyethylene glycol-block-poly (D,L-lactic acid)-DAP (GPP/PP-DAP). In particular, the purity of separated DAP was up to 98.12% for preparation research. GPP/PP-DAP was successfully prepared by the thin-film hydration method. Subsequently, the GPP/PP-DAP was optimized by univariate analysis and the response surface methodology, producing a stable and systemically injectable nano-preparation. Impressively, on the one hand, cytotoxicity studies showed that the IC50 of the GPP/PP-DAP was lower than that of free DAP. On the other hand, the GPP/PP-DAP was more likely to be endocytosed by HepG2 cells and targeted to the liver with orthotopic tumors, potentiating the therapeutical efficacy in HCC. Collectively, both in vitro and in vivo results indicated the excellent tumor inhibition and liver targeting of GPP/PP-DAP, suggesting the nano-preparation could serve as a potential drug delivery system for natural ingredients with anti-hepatoma activity to lay the theoretical foundation for clinical application.
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