| Phlorizin is a kind of dihydrochalcone,which first found and isolated from apple,phlorizin is widely found in Rosaceae plants,abundant exist in Malus spectabilis and docynia,recent studies show that lithocarpus polystachyus rehd and Eseye also contain numerous phloridzin.Phloridzin as the world’s first discovery of SGLT inhibitors,can effectively inhibit the reabsorption of glucose in the kidney and small intestine,increase the excretion of glucose,thus decrease blood glucose.Since phlorizin first time separation by Frech scientists in 1835,it always active in diabetes related areas.In recent years,it has been shown that the phlorizin can reduced high level of blood glucose and lipid metabolism in diabetic patients effectively,Treatment of kidney,liver,eyes,bones,nerves and other complications caused by diabetes.The research of phlorizin pharmacokinetics were relative lack now,the aim of present study was to investigate the pharmacokinetics of phlorizin in type two diabetic rats.In the present study,STZ and high calorie diet were used to induce the symptoms of type two diabetes in male Wistar rats.The experiment was carried out in rats fed a diet containing 20% fat,18% sugar and 3% cholesterol in one month to induce insulin resistance,and then intraperitoneal injection of 45 mg/kg STZ,selective destruction of pancreatic beta cells,resulting in high blood glucose.Model validation was performed after one month,found that the FBG,FINS,TC,TG values were found higher than those of the control group.ITT and IPGTT experiments showed that the insulin sensitivity decreased,and the HOMA-IR index was higher than control groupsignificantly,which also proves that the body produces insulin resistance.The results show that the model of type two diabetes mellitus is reasonable and scientific.The experiment was carried out on STZ induced type two diabetes rats with oral administration of phlorizin,the dose was 50,100,200 mg/kg,oral administration of 100 mg/kg to normal rats.Continuous blood collection through the tail vein during 24 hours,blood samples were obtained by hydrolysis of β-Glucuronidase and Sulfatase,exposure of phlorizin and phloretin in the phase two conjugate forms.After HPLC analysis,the data were disposed by DAS2.0.1 to study the pharmacokinetics.The results showed that after oral administration,the concentration of the phlorizin in the blood was very low,and phloretin was the main form.The AUC(0-t)value were 15.88 ± 4.26 mg/L*h,31.64 ± 18.92 mg/L*h and 68.36 ± 23.87 mg/L*h,There is a linear relationship between the AUC(0-t)and the concentration.The half lives of phlorizin were 8.17 ± 12.27 min,0.42 ± 0.33 min and 0.64 ± 0.24 min.The half lives of phloretin were 0.38 ± 0.22 min,0.79 ± 0.19 min and 0.88 ± 0.14 min.Compared with the normal rats,there was significant difference in the pharmacokinetics of the type two diabetic rats,there was no detection of phlorizin in normal rats,the AUC(0-t)of phlorizin and phloretin were increased in T2 D rats,while half-life of the phloretin was reduced.Intravenous injection of 5,10 and 20 mg/kg phlorizin in normal rats,intravenous injection of 10 mg/kg phlorizin in type two diabetic rats,blood was taken from the jugular vein continuously within 4 hours,the same batch samples were directly detected or through enzymatic hydrolysis severally,to investigate the contribution rate of the prototype drugs and the phase two conjugated metabolites,and investigate the difference of pharmacokinetics after intravenous administration between normal and T2 D rats.The bioavailability was calculated by AUC after oral and intravenous administration phlorizin.The results showed that the utilization rate of phlorizin was significantly increased after intravenous administration,increased phlorizin concentrations in the blood after enzyme hydrolysis,and the phloretin was appeared.The AUC(0-t)value of phlorizin befor enzyme hydrolysis were 66.4 ± 39.1mg/L/min,333.1 ± 91.2 mg/L/min and 516.4 ± 249.3 mg/L/min,the AUC(0-t)value of phlorizin after enzyme hydrolysis were 174.3 ± 128.9 mg/L/min,525.3 ± 132.5 mg/L/min and 739.4 ± 355.0 mg/L/min.The AUC(0-t)value of phloretin were 38.8 ± 16.3 mg/L/min,108.0 ± 19.9 mg/L/min and 149.3 ± 82.7 mg/L/min.In three doseage,the phase two metabolism rate were 69.0%,47.4% and 41.9%.The pharmacokinetics of type two diabetic rats were significantly different from those of normal rats,the AUC(0-t)were increase,half-life decrease.The bioavailability was only 5% after oral administration and bioavailability was very low.In this paper,a new method for the construction of type two diabetic rats was established,and accomplish the pharmacokinetics of phlorizin in normal and diabetic rats through oral and intravenous injection.The study was base on phase two metabolism experimental method.The experimental results showed that the bioavailability of phlorizin was very poor,significant phase two metabolism after oral and intravenous administration always exist.There was a significant pharmacokinetics difference of phlorizin and its metabolites in type two diabetic rats and normal rats,so,In the future research and development of the treatment of diabetes mellitus based on phlorizin,we should take the pharmacokinetic test results of diabetes as reference. |
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