Title The Pharmacokinetic and Metabonomics Studies of Jiao-Tai-Pill in the Treatment of Type 2 Diabetes Mellitus
Abstract

Part鈪燚etermination of Contents of Berberine, Cinnamaldehyde and Cinnamic acid in Jiao-Tai-Pill with Different Combinations of its Constitutional Herbs[Objective]To determine the contents of berberine, cinnamaldehyde and cinnamic acid in Jiao-Tai-Pill with different combinations of its constitutional herbs, for providing precise dosage standards for the following researches of pharmacokinetic and metabonomics of Jiao-Tai-Pill.[Methods]Reversed phase high performance liquid chromatography method (RP-HPLC) was used to determine the contents of berberine, cinnamaldehyde and cinnamic acid in Jiao-Tai-Pill (JTP) with different combinations of its constitutional herbs. Then the dissolution rates of the three effective components in JTP with different compatibility proportions were compared.[Results]The dissolvability ratio of berberine in Rhizoma Coptidis Granules (HLKL), Jiao-Tai-Pill sample one (Rhizoma Coptidis Granules:Cinnamon Granules=1:0.50, JTP1), Jiao-Tai-Pill sample two (Rhizoma Coptidis Granules:Cinnamon Granules=1:0.25, JTP2), Jiao-Tai-Pill sample three (Rhizoma Coptidis Granules:Cinnamon Granules=1:0.10, JTP3) was 12.393% ,11.926% ,12.012% respectively. The dissolvability ratio of cinnamaldehyde in Cinnamon Granules (RGKL), JTP1, JTP2, JTP3 was 4.217%,4.185% ,4.106%,4.021% respectively. The dissolvability ratio of cinnamic acid in RGKL, JTP1, JTP2, JTP3 was 0.322% ,0.317%,0.302%,0.300% respectively.[Conclusion]The dissolvability ratio of berberine, cinnamaldehyde and cinnamic acid with different constituents keep stable though the ratio of in Rhizoma Coptidis and Cinnamon changes. Part鈪erberine and Cinnamic Acid Pharmacokinetics of Jiao-Tai-Pill with Different Combinations of Rhizoma Coptidis Granules and Cinnamon Granules in SD Rats[Objective]To study the pharmacokinetics of berberine and cinnamic acid in Jiao-Tai-Pill with different combinations of Rhizoma Coptidis Granules and Cinnamon Granules in SD rats.[Methods]The concentration of berberine and cinnamic acid in plasma was determined directly by reversed phase high performance liquid chromatography (RP-HPLC) after an oral administration of Jiao-Tai-Pill with different combinations of Rhizoma Coptidis Granules and Cinnamon Granules. The plasma concentration-time curves were plotted. The main pharmacokinetic parameters were obtained. The relative bioavailability of berberine and cinnamic acid in Jiao-Tai-Pill with different combinations of Rhizoma Coptidis Granules or Cinnamon Granules was compared.[Results]The plasma concentration-time curve of berberine and cinnamic acid were discribed by a first-order kinetics and two-compartment model. The relative bioavailability of berberine was 198.49% in JTP1,168.42% in JTP2 and 131.48% in JTP3, respectively. The relative bioavailability of cinnamic acid was 145.34% in JTP1,175.69% in JTP2 and 203.16% in JTP3 respectively. There are obvious differences between HLKL and JTPs in the pharmacokinetic parameters as Cmax, AUC0锝炩垶and Tmax of berberine. Cmax and AUC0锝炩垶of JTP1 is the largest. Similarly there are obvious differences between HLKL and JTPs in the pharmacokinetic parameters as Cmax, AUC0锝炩垶and Tmax of cinnamic acid. Cmax and AUC0锝炩垶of JTP3 is the largest.[Conclusion]Rhizoma Coptidis Granules combined with Cinnamon Granules can increase the relative bioavailability of berberine and cinnamic acid in SD rats.Part鈪harmacokinetics of Berberine and Cinnamic Acid in Healthy Volunteers after Oral Administration of Jiao-Tai-Pill[Objective]To investigate the pharmacokinctics of berberine and cinnamic acid of Jiao-Tai-Pill in healthy Chinese volunteers.[Methods]Ten male volunteerrs were given a single oral administration of Jiao-Tai-Pill with the content of Rhizoma Coptidis Granules was the double of and Cinnamon Granules. The concentrations of berberine and cinnamic acid in plasma were determined by reversed phase high performance liquid chromatography (RP-HPLC). The pharmacokinetic parameters were calculated by DAS (Drug and Statistics) 2.0 pharmacokinetic program.[Results]The plasma concentration time profiles of berberine and cinnamic acid were best fitted with first-order kinetics and two-compartment model. The main pharmacokinetic parameters of berberine and cinnamic acid after a single oral administration of Jiao-Tai-Pill were as follows:AUC0锝炩垶were 1916.427卤99.350 and 2098.627卤39.781渭g路h/L; Cmax were 364.105卤45.130 and 496.627卤36.419渭g/L; Tmax were 1.500卤0.014 and 1.000卤0.008 h; t1/2 were 4.727卤0.124 and 2.883卤0.274 h, CLz/F were 57.709卤3.009 and 0.624卤0.010 L/(h路kg), Vz/F were 329.509卤9.134 and 2.506卤0.548 L/kg, respcctivcly.[Conclusion]Berberine and cinnamic acid is quickly absorbed and slowly cleared when JTP is taken orally. The effective blood drug concentration can be maintained for a long time.Part IV Application of 1H-MRS to Evaluate the Effects of Jiao-Tai-Pill on Hepatic Triglyceride Content in Type 2 Diabetes Mellitus Patients[Objective]To study the application of proton magnetic resonance spectroscopy (‘H-MRS) to evaluate the effects of Jiao-Tai-Pill on hepatic triglycercide content (HTC) in type 2 diabetes mellitus patients.[Methods]Forty type 2 diabetic patients with poor glycemic control were divided into Jiao-Tai-Pill treatment group (T group) and control group(C group) randomly. Blood pressure (BP), body mass index (BMI), waist circumference (WC) and waist to hip ratio (WHR) were examined. The serum alanine aminotransferase (ALT), aspartate Aminotransferase (AST), the concentration of fasting plasma glucose(FPG), fasting insulin (FINS), glycosylated hemoglobin (HbA1C), postprandial 2 hours blood glucose (2hPPG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglyceride(TG) were tested simultaneously. HTC was measured by 1H-MRS scans of the liver. Patients in T group added were taken JTP besides their previous anti-diabetic agents for 12 weeks, and C group patients continued to previous treatment scheme unchanged. All the above parameters were retested after treatment.[Results] There were no significant difference between T group and C group on all the clinical trial. However, at the end of 12-week period BMI, WC,2hPPG, WHR, FINS, FPG, HbA1C, TC, LDL-C and HTC were markedly decreased in patients of T group, HDL-C was increased significantly.[Conclusion]Jiao-Tai-Pill is effective in reducing HTC as well as ameliorating the disturbance of glucose and lipid in type 2 diabetes mellitus patients.Part V Plasma Metabonomics Study of Jiao-Tai-Pill in the Treatment of Type 2 Diabetes Mellitus Rats[Objective]To study the plasma metabonomics of Jiao-Tai-Pill in the treatment of type 2 diabetes mellitus rats[Methods]The rats’models of T2DM were established by the intravenous injection of low-dose streptozotocin (STZ,30mg/kg) and high sucrose-fat diet. Then the animals were divided into model group, HLKL group, RGKL group and JTP group randomly. The corresponding therapy was administered through gastric feeding. Normal rats fed with common chow were designated as normal group. Eight weeks later, the plasma was tested with 1H-MRS technology. The spectra were edited and the principal component analysis (PCA) was applied to determine metabonomics differences among the above groups.[Results]Compared with the normal group, the levels of glucose, lactate, taurine, pyranicacid,尾-hydroxybutyric acid, acetoacetate, succinic acid, citric acid, LDL, glutamine, alanine and methionine were significantly higher in the plasma of the model group. Compared with the HLKL group, the levels of glucose, succinic acid, citric acid were significantly higher in the plasma of the model group. Compared with the RGKL group, the levels of Glucose, lactate, taurine, pyranicacid, (3-hydroxybutyric acid, acetoacetate, LDL were significantly higher in the plasma of the model group. Compared with the HLKL group, the levels of lactate, taurine were significantly higher, and pyranicacid,尾-hydroxybutyric acid, acetoacetate, LDL, succinic acid, citric acid were significantly lower in the plasma of the RGKL group. Compared with the JTP group, the levels of glucose, lactate, taurine, pyranicacid,尾-hydroxybutyric acid, acetoacetate, succinic acid, citric acid, LDL, glutamine, alanine and methionine were significantly higher in the plasma of the model group.[Conclusion]Severe glucose and lipid metabolism disorders were found in diabetic rats. JTP, HLKL and RGKL significantly affect plasma metabonomics in T2DM rats. It is suggested that Rhizoma coptidis may affect the certain process of the tricarboxylic acid cycle (TCA) to promote glucose aerobic oxidation, while Cinnamomum cassia may mainly promote glucose anaerobic glycolysis. In addition, JTW seemly might be affects the procedure of gluconenogenesis. These might be one of compatibility rationality of compatibility rationality of Rhizoma coptidis and Cinnamomum.Part VI Plasma Metabonomics Study of Jiao-Tai-Pill in the Treatment of Type 2 Diabetes Mellitus Patients[Objective]To study the plasma metabonomics of Jiao-Tai-Pill in the treatment of type 2 diabetes mellitus patients[Methods] Twenty type 2 diabetes mellitus patients with poor glycemic control and 20 healthy volunteers were recruited. JTP was taken orally in diabetic patients for 12 weeks. Blood samples were taken before and after the treatmet. The plasma was collected after centrifugalization. The low molecular mectabolites and lipid in plasma were examined by 1H-MRS technology. The spectra were edited and principal component analysis (PCA) was applied to make determine metabonomics differences between T2DM subjects and healthy volunteers, or between before treatment and after treatment by JTP in subjects.[Results]Compared with healthy volunteers, the levels of glucose, glycoprotein, pyranicacid, (3-hydroxybutyric acid, acetoacetate, LDL, creatinine, glycine were significantly higher, and lactate, taurine, succinic acid, citric acid, glutamine, alanine, methionine, valine were significantly lower in the plasma of T2DM subjects. Compared with before treatment by JTP, the levels of glucose, glycoprotein, pyranicacid,尾-hydroxybutyric acid, acetoacetate, LDL, were significantly lower, and citric acid, succinic acid, glutamine, alanine, methionine, valine were significantly higher in the plasma of T2DM subjects at the end of 12-week period.[Conclusion]Severe glucose and lipid metabolism disorders were found in diabetic patients. JTP significantly affect plasma metabonomics in T2DM patients. It is suggested that JTP may affect the certain process of the tricarboxylic acid cycle (TCA) to promote glucose aerobic oxidation, In addition, JTW seemly might be affects the procedure of gluconenogenesis. But JTW has little influence to glycolysis in T2DM subjects unlike in T2DM rats

Category TCM
Keywords Berberine, Cinnamaldehyde, Cinnamic acid, Cinnamomum cassia, compatibility, Jiao-Tai-Pill, Reversed phase high performance liquid chromatography, Rhizoma coptidis,
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