Quality Control And Therapeutic Drug Monitoring On SD Rat Of Innovative Drugs GDH

GDH a synthesis flavonol glycosides compounds.GDH can obviously lower the contents of TC、LDL-C、ApoB 100 and ox-LDL in serum of hyperlipidemic animal model, have the effect of treatment of hyperlipemia. Up to now, GDH is in the stage of preclinical-study.The quality control and pre-clinical pharmacokinetic research data of GDH has not been reported in recent years. This study was designed to control the quality of GDH according to Pharmacopoeia and related regulations, The pharmacokinetic study was conducted by oral administration of a single dose of the three dose groups (low, medium and high doses) according to the determined optimum dose from pharmacodynamic study of GDH raw medicine,to provide a reference for drug declaring and further clinical application.1. Studies on quality control of GDHQuality research on GDH raw medicine mainly includes characters and physicochemical constants, identification, inspection and assay.Characters and physicochemical constants:The results showed that GDH is light yellow powder of osteoporosis, odorless, slightly moist, specific rotation is -63°～ -73°,freely soluble in dimethyl sulfoxide(DMSO) and n n-dimethylformamide(DMF), slightly soluble in methanol, acetoneand acetonitrile, very slightly soluble in ethanol, hardly soluble in ether and water.Through ultraviolet spectrum (UV), chemical method and high performance liquid chromatography (HPLC) method for qualitative identification, results show that standard substances and test samples have the same spectral characteristics, Maximum UV absorption wavelengths were 245nm and340nm,HCl-Mg reaction colorimetry show orange-red,the consistent retention time between main peak of test samples and standard substances.Inspection:Studied the moisture determination, loss on drying, related substances, residual organic solvents, ignition residue, heavy metals, arsenic salt and so on. The results indicated that the result of moisture determination was within 8%, drying wet weight reduction from3.54%～4.15%.The results of residue on ignition showed that the residue of the product after ignition temperature was within 0.2%. Heavy metal does not exceed twenty millionths, but exceed tenty millionths. Arsenic test results show that arsenic salt does not exceed 0.0002%.The reasarch of related substances showed that GDH only contains a impurities, and the impurities was the precursor compound of GDH which through structural identification was FG-1. The related substances of GDH could be determined with correction factors, the correction factors was 0.45. Each single impurity was lower than 3.0%.The result of residual organic solvents showed that had a litte ethanol residue in GDH, but is less than regulations limitation,conform to the rules.Assay:The content of GDH raw medicines were determined by high performance liquid chromatography (HPLC), and studied the methodology, the method is feasible. The final content of GDH raw medicines (calculated on the basis of anhydrous), were 98%～102%.2. Therapeutic dug monitoring of GDHA rapid and sensitive LC-MS/MS assay method has been established for determination of biological samples after protein precipitation procedure. The methodology validation was accomplished in accordance with the guiding principle of "non-clinical studies of chemical drugs" measured specificity, linearity, accuracy, precision, recovery, stability etc. and all meet the requirements of the quantitative analysis of a biological sample.The pharmacokinetic studies have been developed by single dose oral administration of GDH raw medicine as 15mg/Kg,30mg/Kg and60mg/Kg in SD rats and the GDH concentrations were determined by LC-MS/MS at different time points. Non-compartment model was selected to calculate and estimate the pharmacokinetic parameters of GDH raw medicine. The elimination half-life (t1/2) was 4.97±0.87h、4.78±1.17h、4.08±0.42h, mean residence time (MRT) was 7.75±0.91h、6.86±0.94h、8.73±0.75h, the peak concentration (Cmax1) and (Cmax2) was217.42±52.49ng/mL.303.77±120.88ng/mL、280.55±82.21 ng/mL and 267.28 ±35.41 ng/mL、415.32±65.62ng/mL、633.76±54.69ng/mL, AUC0～36 was 1689.92±238.89ng·h/mL、3039.54±876.59 ng·h/mL、5268.98±534.99ng·h/mL, AUC0～∞ was 1699.86±237.6ng·h/mL、3054.14±871.13ng·h/mL、5281.89±535.98 ng·h/mL. AUCo～36 and Cmax of GDH were positively correlated with the doses and the correlation coefficinets which were r2=0.8737and r2=0.8994 respectively.