The Intestinal Absorption Of The Norcantharidin Adamantane Derivative(SU2162)

The title compound SU2162, is synthesized in DMF by an imidization reaction using amantadine and norcantharidin as raw material. The result of pharmacodynamics indicated that it has the remarkable inhibitory effect on glioma growth(IC 50 =0.721umol/L). The experimental group of Prof. Zai You Tan had not only optimized the Synthesis, but also published articles about the stuctures[3,4],preparations and mutual transformation of two crystal forms [5,6], simultaneously studied on the pharmacokinetics and tissue distribution of SU2162 after intravenous administration[7,8].Based on the above researches, the thesis was to study the physico-chemical properties and intestinal absorption kinetics of SU2162. The results were as follows:1. The chromatographic condition of TLC identification for SU2162 has been built: GF254 SC-SIB was used to be a stationary phase, MSO: ethyl acetate(1:1) and the wagner reagent respectively were regarded as a developing solvent and a developer. The condition was effective under the daylight view, whose dosage was 5μL. SU2162 was characterized as a pure substance through TLC and IR methods. The crystal form was verified by capillary tube, DSC and PXRD.2. The study of physicochemical properties of SU2162 has been accomplished. The solubility and menbrane permeability were determined to provide the basis for further experiments, and their intracorporal absorption were predicted. SU2162 was low water-solubility,but had well menbrane permeability with log P of 1.3918 in octanol/water system.The distribution coefficients in the p H2.0、4.0、5.8、6.8、7.4、8.0、9.18 of buffer solution respectively were 1.6812、1.6812、1.5480、1.4561、1.1252、1.1542、1.1308,which indicated that SU2162 had good permeability in gastrointestinal tract.3. A selective and sensitive high-performance liquid chromatography method has been developed and validated for determination of SU2162 in perfusion solution. Chromatographic separation was achieved on a Phenomine Genimi C18 column(250 mm× 4.6 mm) using acetonitrile and water(60:40) as mobile phase at a flow rate of 1.0 ml·min- 1. The assay was linear in the range of 1.0-40.0 μg·m L- 1 with a correlation coefficient of 0.9998. Limits of detection and quantification were 0.06 μg·m L-1 and 0.20 μg·m L-1, respectively. The intra-day precision of the method was 8.01%(low), 3.76%(middle), 1.91%(high) respectively. The inter-day precision of the method was 5.88%(low), 0.83%(middle) and 0.88%(high) respectively. The accuracy of the method was 102.50%(low), 99.43%(middle) and 104.29%(high), respectively. All above parameters were acceptable[9]. The results of different stability measurement showed that SU2162 had high stability.4. The intestinal absorption of SU2162 in rat was detected to investigate the influence in different position absorption and the samples concentration of SU2162 were determined by HPLC. The absorption rate constant(Ka) and the apparent permeability coefficients(Papp) among duodenum, jejunum and ileum showed no significant differences respectively(P>0.05),which illustrated the intestine absorbed SU2162 well with no obvious absorption parts.