新型Hsp90抑制剂-SNX-2112的临床前药代动力学研究
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摘要
SNX-2112是近几年筛选出的一种新型Hsp90抑制剂,经体内、外实验证明SNX-2112具有良好的抗肿瘤作用,能显著延长荷瘤动物的生存期,是一种具有开发前景的抗肿瘤药物。
本研究主要进行了以下几方面的工作：1.建立了HPLC测定SNX-2112含量的方法。2.建立了SNX-2112在生物样品中的分离与测定方法。3.研究了SNX-2112的药代动力学。采用建立的SNX-2112生物样品测定方法进行了大鼠药代动力学实验,探讨了SNX-2112在大鼠体内动态变化的规律及其特点。
结果表明,SNX-2112在大鼠体内的动力学符合二室模型。单次给药2.5,5, 10mg/kg后,三个剂量组的浓度-时间曲线下面积(AUC)分别为：7.62±1.03,8.10±0.77,15.80±1.00 (μg/ml)*h;分布半衰期t1/2a分别为：0.63±0.09,0.38±0.03,0.51±0.06h；消除半衰期t1/2β分别为：9.96±4.32,10.43±4.06,10.41±4.38h。在分布实验中,采用HPLC法测定单次SNX-2112(10mg/kg)静脉注射给药后大鼠各组织中原形药物在4个不同时间点的浓度,其结果表明SNX-2112在体内分布较广泛而迅速,其中以肝分布最多。在排泄实验中,大鼠尾静脉注射SNX-2112(10mg/kg)后,用HPLC法测定表明,原形药物的排泄量依次为粪便>尿液>胆汁；本实验还测定了SNX-2112对大鼠肝药酶的影响。此外,本实验还用超滤法测得了SNX-2112与大鼠及人的血浆蛋白结合率,并对SNX-2112的代谢做了初步研究。以上实验为该化合物的临床研究提供了科学依据。
SNX-2112 is a novel screened Hsp90 inhibitor in recent years, Many experiments, both in vivo and in vitro, have proved its significant antitumor effect. Currently SNX-2112 is considered to be a promising anti-cancer drug for exploring.
The work developed in this dissertation were as follows:
1. Developed a method for the determination of SNX-2112.2. Developed a method for determination of SNX-2112 in the biological samples.3. The pharmacokinetics of SNX-2112 were studied. The results showed that the pharmaco-kinetics of SNX-2112 in rats plasma agreed with two-compartment model. After i.v. administration of SNX-2112 with 10 mg/kg, the terminate half-life of SNX-2112 was 10.41±4.38h. The parameters of another two dosage groups (2.5 mg/kg,5 mg/kg) were similar.
The distribution study of SNX-2112 in rats showed that SNX-2112 could be extensively after i.v. administration with 10mg/kg, and it is distributed in liver at most. After i.v. administration with 10mg/kg, the samples of urine, and bile in rats were analyzed by HPLC. The study showed that the origin form of SNX-2112 was mainly excreted via fece. The experiment also measured the effects of SNX-2112 on hepatic drug metabolizing enzymes. In addition, this study also measured plasma protein binding rates of SNX-2112 with rat plasma and human plasma using ultrafiltration, the metabolism of SNX-2112 has been done a preliminary study.
These experiments of the compound provided a scientific basis for clinical research in the future.
本研究主要进行了以下几方面的工作：1.建立了HPLC测定SNX-2112含量的方法。2.建立了SNX-2112在生物样品中的分离与测定方法。3.研究了SNX-2112的药代动力学。采用建立的SNX-2112生物样品测定方法进行了大鼠药代动力学实验,探讨了SNX-2112在大鼠体内动态变化的规律及其特点。
结果表明,SNX-2112在大鼠体内的动力学符合二室模型。单次给药2.5,5, 10mg/kg后,三个剂量组的浓度-时间曲线下面积(AUC)分别为：7.62±1.03,8.10±0.77,15.80±1.00 (μg/ml)*h;分布半衰期t1/2a分别为：0.63±0.09,0.38±0.03,0.51±0.06h；消除半衰期t1/2β分别为：9.96±4.32,10.43±4.06,10.41±4.38h。在分布实验中,采用HPLC法测定单次SNX-2112(10mg/kg)静脉注射给药后大鼠各组织中原形药物在4个不同时间点的浓度,其结果表明SNX-2112在体内分布较广泛而迅速,其中以肝分布最多。在排泄实验中,大鼠尾静脉注射SNX-2112(10mg/kg)后,用HPLC法测定表明,原形药物的排泄量依次为粪便>尿液>胆汁；本实验还测定了SNX-2112对大鼠肝药酶的影响。此外,本实验还用超滤法测得了SNX-2112与大鼠及人的血浆蛋白结合率,并对SNX-2112的代谢做了初步研究。以上实验为该化合物的临床研究提供了科学依据。
SNX-2112 is a novel screened Hsp90 inhibitor in recent years, Many experiments, both in vivo and in vitro, have proved its significant antitumor effect. Currently SNX-2112 is considered to be a promising anti-cancer drug for exploring.
The work developed in this dissertation were as follows:
1. Developed a method for the determination of SNX-2112.2. Developed a method for determination of SNX-2112 in the biological samples.3. The pharmacokinetics of SNX-2112 were studied. The results showed that the pharmaco-kinetics of SNX-2112 in rats plasma agreed with two-compartment model. After i.v. administration of SNX-2112 with 10 mg/kg, the terminate half-life of SNX-2112 was 10.41±4.38h. The parameters of another two dosage groups (2.5 mg/kg,5 mg/kg) were similar.
The distribution study of SNX-2112 in rats showed that SNX-2112 could be extensively after i.v. administration with 10mg/kg, and it is distributed in liver at most. After i.v. administration with 10mg/kg, the samples of urine, and bile in rats were analyzed by HPLC. The study showed that the origin form of SNX-2112 was mainly excreted via fece. The experiment also measured the effects of SNX-2112 on hepatic drug metabolizing enzymes. In addition, this study also measured plasma protein binding rates of SNX-2112 with rat plasma and human plasma using ultrafiltration, the metabolism of SNX-2112 has been done a preliminary study.
These experiments of the compound provided a scientific basis for clinical research in the future.
引文
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