Study on the Safety of the Low Glucoside Composites from Epimedii Folium and Pharmacokinetics of Its Five Low Glucosides / 中药新药与临床药理

ABSTRACT

Objective To evaluate the safety of the low glucoside composites of Epimedii Folium and clarify the pharmacokinetic characteristics of its five low glucosides.Methods Four groups of KM mice were orally administrated of corn oil,1 968,2 625 and 3 500 mg·kg-1 low glucoside composites of Epimedii Folium,respectively.Then,the living conditions,toxic symptoms,and death of the mice were observed for 7 consecutive days.After the mice were dissected,the viscera/body ratio and the viscera/brain ratio were calculated.Besides,the contents of alanine aminotransferase(ALT)and aspartate transaminase(AST)in plasma were determined by ELISA,and the pathological changes of the liver were observed by HE staining.C57BL/6J mice were intravenously or orally administered of baohuoside I,baohuoside II,sagittatoside A,sagittatoside B and sagittatoside C.Then,blood samples were collected at different time points.The plasma concentrations of the five low glucosides were measured by UHPLC-MS/MS.Results When compared with the control group,no significant differences were found in the body mass,viscera/body ratio,viscera/brain ratio,contents of ALT and AST in plasma after oral administration of different doses of low glucoside composites to mice.Moreover,no pathological changes or damages were found in the liver sections.After intravenous injection,the AUC0-t values of baohuoside Ⅰ,baohuoside Ⅱ,sagittatoside A,sagittatoside B and sagittatoside C in mice were 4.82,82.54,276.64,88.77 and 178.02 min·μg·mL-1,respectively.Meanwhile,the t1/2 values were 60.42,115.27,67.63,131.61 and 129.87 min,respectively.After oral administration,the AUC0-t values of the five low glucosides were 31.64,18.59,3.48,2.41 and 2.42 min·μg·mL-1,respectively.The Cmax values were 147.23,86.76,15.58,24.34 and 26.12 ng·mL-1,respectively.The tmax values were 21.00,78.00,78.00,30.00 and 28.00 min,respectively.The bioavailability of baohuosideⅠ,baohuosideⅡ,sagittatoside A sagittatoside B and sagittatoside C were 1.91%,0.51%,0.05%,0.06%and 0.04%,respectively.Conclusion The low glucoside composites of Epimedii Folium has high safety,and no hepatotoxicity were observed at dose of 3 500 mg·kg-1.The 5 low glucosides are quickly absorbed and rapidly eliminated in mice,and all of them have low bioavailability.