二-（4-甲氧基-苯甲酰异羟肟酸）二正丁基合锡（DBDMT）的代谢动力学研究
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摘要
本文探讨了有机锡抗癌化合物二-(4-甲氧基-苯甲酰异羟肟酸)二正丁基合锡(DBDMT)在大鼠体内的代谢动力学过程。
第一部分为DBDMT在小鼠体内的急性毒性试验,通过Bliss法测定小鼠静脉注射DBDMT后半数致死量(LD_(50)),结果表明小鼠静脉注射DBDMT的LD_(50)为15.3mg/kg,LD_(50)(Feiller校正)95%的可信限为13.67-17.159mg/kg,LD_(50)的标准误差为0.007。其主要毒性靶器官可能为脑、肾、心脏及脾等。本研究工作为DBDMT大鼠体内药代动力学研究给药剂量提供依据。
第二部分建立了RP-HPLC测定血浆中DBDMT的方法并研究了DBDMT在大鼠体内的吸收动力学过程。建立了血浆样品的预处理方法,通过色谱条件筛选,采用甲醇-水(25:75,用H3PO4调节pH至3.0)为流动相,检测波长为251nm,流速为1ml/min的RP-HPLC法以测定大鼠血浆中DBDMT浓度。在此色谱条件下,DBDMT在187.5~24000ng/ml的浓度范围内,DBDMT的浓度与其样品峰面积和内标峰面积之比线性关系良好(r = 0.9996),检测限为3.1ng ( S/N=3 );低(400ng/ml)、中(2000ng/ml)、高(20000ng/ml)三个浓度的日内和日间精密度的RSD均小于10.0%;低(400ng/ml)、中(2000ng/ml)、高(20000ng/ml)三个浓度的提取回收率分别为96.6%,96.9%,99.7%。以静脉给药方式进行的吸收动力学实验结果表明,DBDMT在大鼠体内的动力学过程符合二室模型,单次给药2、5、10.7mg/kg后,三个剂量组的浓度-时间曲线下面积AUC(0-t)分别为:35142±10744、114931±59087和171866±51349 ng·mL~(-1)·min;分布半衰期t_(1/2(α))分别为:1.923±0.561、1.930±0.519和2.424±1.027min;消除半衰期t_(1/2(β))分别为:15.523±2.881、33.100±20.769、26.088±9.081min。试验结果表明,大鼠单剂量尾静脉注射DBDMT后,分布及消除速度快,其体内过程符合二室模型。
第三部分研究了DBDMT在大鼠体内的组织分布、排泄等动态变化的规律及特点。建立了各个组织样品和胆汁、尿液及粪便排泄物样品的预处理方法。色谱条件为:流动相为甲醇-水(16:84,用H3PO4调节pH至3.0),检测波长为251nm,流速为1ml/min。在此色谱条件下,大鼠各组织中DBDMT在200~1600ng/ml范围内线性关系良好。样品平均回收率大于90%,RSD小于10%。日内精密度RSD小于10%,日间精密度RSD小于10%。胆汁、尿液、粪便样品平均回收率大于70%,RSD小于10%。在组织分布实验中,采用HPLC法测定单次DBDMT(5mg/kg)静脉注射给药后大鼠各组织中原型药物在4个不同时间点的浓度。结果显示,DBDMT能通过血脑屏障,分布于脑组织,主要分布于脑、心脏、肾、脾、肌肉等组织,给药3min后DBDMT已迅速分布到各个组织中,给药10min和30min后,DBDMT浓度已明显下降,12h后各组织器官和血浆中均检测不到DBDMT,说明原型化合物在各个组织器官中无蓄积现象。在排泄实验中,采用HPLC法测定单次DBDMT( 5 mg/kg)静脉注射给药后胆汁、尿液及粪便中原型化合物在不同时间段的浓度,均检测不到原型化合物,说明DBDMT最终不以原型化合物的形式排泄,而主要是以代谢物的形式排泄。
第四部分测定DBDMT与大鼠血浆蛋白的结合率。采用平衡透析法,用HPLC法分别测定高(20000ng/ml)、中(2000ng/ml)、低(400ng/ml)三种不同浓度的DBDMT的血浆蛋白结合率。高、中、低三种不同浓度的DBDMT的血浆蛋白结合率分别为28.03%,43.87%,45.64%。
The objective of this study is to investigate the pharmacokinetics of anticancer organotin compound (n-Bu)_2Sn[C_7H_5NO_2(MeO)_2]_2(DBDMT)in rats.
In the first party the acute toxicity of DBDMT in the mice was studied. The median lethal dose(LD_(50)) of DBDMT injection to mice was determined by Bliss method. The LD_(50) was 15.3mg/kg, 95% confidence limit was 13.67~17.159mg/kg, and the standard error of LD_(50) was 0.007. The organs such as heart, kidney, brain, spleen and so on perhaps were the main toxic organs. The LD_(50) 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 187.5~24000ng/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.
第一部分为DBDMT在小鼠体内的急性毒性试验,通过Bliss法测定小鼠静脉注射DBDMT后半数致死量(LD_(50)),结果表明小鼠静脉注射DBDMT的LD_(50)为15.3mg/kg,LD_(50)(Feiller校正)95%的可信限为13.67-17.159mg/kg,LD_(50)的标准误差为0.007。其主要毒性靶器官可能为脑、肾、心脏及脾等。本研究工作为DBDMT大鼠体内药代动力学研究给药剂量提供依据。
第二部分建立了RP-HPLC测定血浆中DBDMT的方法并研究了DBDMT在大鼠体内的吸收动力学过程。建立了血浆样品的预处理方法,通过色谱条件筛选,采用甲醇-水(25:75,用H3PO4调节pH至3.0)为流动相,检测波长为251nm,流速为1ml/min的RP-HPLC法以测定大鼠血浆中DBDMT浓度。在此色谱条件下,DBDMT在187.5~24000ng/ml的浓度范围内,DBDMT的浓度与其样品峰面积和内标峰面积之比线性关系良好(r = 0.9996),检测限为3.1ng ( S/N=3 );低(400ng/ml)、中(2000ng/ml)、高(20000ng/ml)三个浓度的日内和日间精密度的RSD均小于10.0%;低(400ng/ml)、中(2000ng/ml)、高(20000ng/ml)三个浓度的提取回收率分别为96.6%,96.9%,99.7%。以静脉给药方式进行的吸收动力学实验结果表明,DBDMT在大鼠体内的动力学过程符合二室模型,单次给药2、5、10.7mg/kg后,三个剂量组的浓度-时间曲线下面积AUC(0-t)分别为:35142±10744、114931±59087和171866±51349 ng·mL~(-1)·min;分布半衰期t_(1/2(α))分别为:1.923±0.561、1.930±0.519和2.424±1.027min;消除半衰期t_(1/2(β))分别为:15.523±2.881、33.100±20.769、26.088±9.081min。试验结果表明,大鼠单剂量尾静脉注射DBDMT后,分布及消除速度快,其体内过程符合二室模型。
第三部分研究了DBDMT在大鼠体内的组织分布、排泄等动态变化的规律及特点。建立了各个组织样品和胆汁、尿液及粪便排泄物样品的预处理方法。色谱条件为:流动相为甲醇-水(16:84,用H3PO4调节pH至3.0),检测波长为251nm,流速为1ml/min。在此色谱条件下,大鼠各组织中DBDMT在200~1600ng/ml范围内线性关系良好。样品平均回收率大于90%,RSD小于10%。日内精密度RSD小于10%,日间精密度RSD小于10%。胆汁、尿液、粪便样品平均回收率大于70%,RSD小于10%。在组织分布实验中,采用HPLC法测定单次DBDMT(5mg/kg)静脉注射给药后大鼠各组织中原型药物在4个不同时间点的浓度。结果显示,DBDMT能通过血脑屏障,分布于脑组织,主要分布于脑、心脏、肾、脾、肌肉等组织,给药3min后DBDMT已迅速分布到各个组织中,给药10min和30min后,DBDMT浓度已明显下降,12h后各组织器官和血浆中均检测不到DBDMT,说明原型化合物在各个组织器官中无蓄积现象。在排泄实验中,采用HPLC法测定单次DBDMT( 5 mg/kg)静脉注射给药后胆汁、尿液及粪便中原型化合物在不同时间段的浓度,均检测不到原型化合物,说明DBDMT最终不以原型化合物的形式排泄,而主要是以代谢物的形式排泄。
第四部分测定DBDMT与大鼠血浆蛋白的结合率。采用平衡透析法,用HPLC法分别测定高(20000ng/ml)、中(2000ng/ml)、低(400ng/ml)三种不同浓度的DBDMT的血浆蛋白结合率。高、中、低三种不同浓度的DBDMT的血浆蛋白结合率分别为28.03%,43.87%,45.64%。
The objective of this study is to investigate the pharmacokinetics of anticancer organotin compound (n-Bu)_2Sn[C_7H_5NO_2(MeO)_2]_2(DBDMT)in rats.
In the first party the acute toxicity of DBDMT in the mice was studied. The median lethal dose(LD_(50)) of DBDMT injection to mice was determined by Bliss method. The LD_(50) was 15.3mg/kg, 95% confidence limit was 13.67~17.159mg/kg, and the standard error of LD_(50) was 0.007. The organs such as heart, kidney, brain, spleen and so on perhaps were the main toxic organs. The LD_(50) 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 187.5~24000ng/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.
引文
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