Pharmacokinetic Study Of Puerarin In Type ? Diabetic Rats

Objective:Puerarin,an isoflavonoid extracted from Puerarin lobata roots,displays a broad range of pharmacological activities,including antidiabetic activity.However,there is few information about the pharmacokinetics of puerarin in type ? diabetics.This study was conducted to investigate the difference in pharmacokinetic effects of puerarin in normal rats,HFD rats and DM rats.Methods:Rats were divided into three groups,DM groups,HFD groups and CON groups.Type ? diabetes was induced by the combine of HFD and STZ injection.HFD rats were induced only by the HFD.Plasma concentrations of puerarin in DM,HFD,and CON groups were determined after intravenous?20 mg/kg?and oral administration?500 mg/kg?of puerarin,and pharmacokinetic parameters were also estimated.The messenger RNA?mRNA?and protein expression levels of Ugt1a1 and Ugt1a7 in rat livers and intestines were measured using qRT-PCR and Western Blot,respectively.Results:Our study have successfully established type ? diabetic rats through HFD and STZ.In addition,we also established an effective analysis HPLC method to detect puerarin in rat plasma.Pharmacokinetic results showed that the mean plasma concentration in the DM group was significantly lower than that in the CON group,either intravenously or orally,and there was no difference in blood concentration between the HFD group and the CON group.Pharmacokinetic parameters,AUC,MRT,and CL_z were significantly different between the CON and DM groups?p<0.05 or p<0.01?.For oral administration,AUC,C_max and t_1/2z of the CON group were significantly higher than those of the DM group,while CL_z and CL_z/F were significantly lower those of the DM group.The results of qRT-PCR showed that the mRNA of Ugt1a1 in the liver and intestine of the DM group was about 3.38 times and 2.81 times higher than that of the CON group,which was 1.34 times and 1.29 times higher than that of the HFD group.Ugt1a7 also reflected a similar trend.The relative expression level of Ugt1a7 mRNA in liver and intestine of DM group was 1.90 times and 1.75 times that of CON group,which was 2.04 times and 2.52 times higher than that of HFD group.These results indicate that the pathological state of type ? diabetes can significantly up-regulate the mRNA expression levels of Ugt1a1 and Ugt1a7 in rats?p<0.05?.Western Blot results showed that the Ugt1a1 protein expression levels in the liver and intestine of the DM group were 2.02 times and 5.43 times higher than that of the CON rats,and were 2.05times and 3.45 times higher than that of the HFD rats.The Ugt1a7 protein expression levels in the liver and intestine of the DM group were 3.96 and 2.07 times higher than those of the CON rats,respectively,and 3.49 and 2.09 times higher than that of the HFD rats.The trend of these results was the same as that in mRNA expression levels,indicating that the expressions of Ugt1a1 and Ugt1a7 in liver and intestine of rats was significantly enhanced under the pathological conditions of diabetes?p<0.05?.Conclusion:The metabolic changes in type ? diabetes can alter the pharmacokinetics of puerarin.This alternation can be caused by the significant increasing of mRNA and protein expression of Ugt1a1 and Ugt1a7,which may enhance the puerarin clearance and alter its therapeutic effects.