| The objective of this study is to investigate the pharmacokinetics of anticancer organotin compound (n-Bu)2Sn[C7H5NO2(MeO)2]2(DBDMT)in rats.In the first party the acute toxicity of DBDMT in the mice was studied. The median lethal dose(LD50) of DBDMT injection to mice was determined by Bliss method. The LD50 was 15.3mg/kg, 95% confidence limit was 13.6717.159mg/kg, and the standard error of LD50 was 0.007. The organs such as heart, kidney, brain, spleen and so on perhaps were the main toxic organs. The LD50 study provided foundation for the further investigation of pharmacokinetics in the rat.The second party is the determination of DBDMT in rat plasma by RP-HPLC and study the absorption pharmacokinetics of DBDMT. The extraction method was chosen to pretreat plasma samples before HPLC analysis. The analytical column was Diamonsil ODS(4.6mm×200mm,5μm). A mobile phase of methanol and water (25:75, pH3) was run at a rate of 1.0 ml/min. The UV detection wave length was 251nm. The calibration curve was linear (r=0.9996) within the range of 187.524000ng/ml for DBDMT. The detection limit was 3.1ng (S/N=3). In the three different concentrations ( low, middle, high) , the mean recovery of DBDMT was 96.6%, 96.9%, 99.7%, respectively; Both of the intra-day and inter-day precision were less than 10.0%. The pharmacokinetics of DBDMT was studied. The results showed that the pharmacokinetics of DBDMT in rat plasma agreed with two-compartment open model. After i.v. administration with 2, 5, 10.7 mg/kg, the AUC(0-t) were 35142±10744, 114931±59087, 171866±51349ng·ml-1·min, the distribution half-life were 1.923±0.561, 1.930±0.519, 2.424±1.027min and the terminate half-life were 15.523±2.881, 33.100±20.769, 26.088±9.081min, repeectively. The experimental data showed that the concentration-time curve of DBDMT in rat plasma could be fitted to two-compartment model. It was also proved that DBDMT was eliminated quickly in blood.The third party is the tissue distribution and excretion of DBDMT in rat. The extraction method was chosen to pretreat the tissues, bile, urine and feces samples before RP-HPLC analysis. The analytical column was Diamonsil ODS(4.6mm×200mm,5μm). A mobile phase of methanol and water (16:84, pH3) was run at a rate of 1.0 ml/min. The UV detection wave length was 251nm. The calibration curve was linear (r>0.99) within the range of 200-1600ng/ml for DBDMT in tissues, the mean recovery of DBDMT was more than 90.0%, both of the intra-day and inter-day precision were less than 10.0%. The mean recovery of DBDMT was more than 70.0% for DBDMT in bile, urine and feces. When rats were injected with DBDMT (5mg/kg) for 3min, DBDMT could be distributed to heart, brain, kidney, muscle and spleen. The concentration of DBDMT would obviously decline after 10 and 30min, there was no accumulation in tissues after 24h. There was also no parent compound of DBDMT to be detected in bile, urine and feces.The fourth party is determination of the plasma protein binding rate of DBDMT. Plasma protein binding rate of DBDMT in three concentrations (20000, 2000, 400ng/ml) were investigated by equilibrium dialysis. The plasma protein binding rate of DBDMT at high, middle, and low were 28.03%, 43.87%, 45.64%, respectively. |
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