消癌平对伊马替尼在大鼠体内外代谢的影响
|
摘要
目的探讨消癌平注射液对伊马替尼在大鼠体内外代谢的影响。方法分别在伊马替尼人和大鼠肝微粒体孵育体系中加入2μl消癌平注射液和消癌平注射液10倍稀释液,孵育结束后终止反应。建立超高效液相色谱-串联质谱(UPLC-MS/MS),检测代谢产物N-去甲基伊马替尼的生成量。将SD大鼠随机分成对照组和给药组(按7.5ml/kg连续10d腹腔注射消癌平注射液),每组8只,消癌平注射液连续给药10d,第10天两组大鼠按30mg/kg灌胃伊马替尼,并于灌胃后0.25、0.5、1、2、4、6、8、12、24h采集血样处理并检测。结果以伊马替尼为底物,消癌平注射液和消癌平注射液10倍稀释液在大鼠肝微粒体中,较对照组分别抑制了90.83%和50.73%;在人肝微粒体中,较对照组分别抑制了79.44%和28.77%。消癌平注射液连续10d腹腔注射后,伊马替尼及其活性代谢产物N-去甲基伊马替尼的相关药代动力学参数发生了改变:相比于空白对照组,血浆伊马替尼达峰时间(T_(max))延后了105.72%,表观分布容积(Vz/F)减少了24.76%;血浆N-去甲基伊马替尼AUC_(0-t)减少了21.37%,AUC_(0-∞)减少了19.29%,Tmax延后了35.70%,峰浓度(C_(max))减少了20.01%,Vz/F增加了45.38%,清除率(CLz/F)增加了32.44%。结论体内外实验结果提示消癌平注射液能影响伊马替尼的代谢。临床上同时应用消癌平注射液与伊马替尼时,应密切关注患者的临床症状和伊马替尼血药浓度Tmax。
Objective To investigate the effect of Chinese medicine Xiaoaiping on metabolism of imatinib in vitro and in vivo.Methods Incubation system of human and rat liver microsomes were added with 2.0μl Xiaoaiping injection or 10 times diluted Xiaoaiping injection,respectively.The amount of N-desmethyl imatinib was determined with UPLC-MS/MS when the reaction was terminated.Sixteen SD rats were randomly divided into control group and Xiaoaiping group with 8 in each group,7.5 ml/kg Xiaoaiping was intraperitoneally injected in Xiaoaiping group for 10 days.At d10 a single dose of 30 mg/kg imatinib was administered intragastrically in both groups,the blood samples were taken at 0.25,0.5,1,2,4,6,8,12 and 24 h after gavage for pharmacokinetic study.Results In vitro study showed that the inhibition rates of Xiaoaiping injection and 10 times diluted Xiaoaiping were 90.83% and 50.73% in rat liver microsomes,those were 79.44% and 28.77% in human liver microsomes.In vivo study showed that compared with control group,in Xiaoaiping group the Tmaxof imatinib was delayed 105.72%,the Vz/F was decreased by 24.76%,AUC_(0-t) of N-desmethyl imatinib was decreased by 21.37%,AUC_(0-∞) of N-desmethyl imatinib was decreased by 19.29%,Tmaxof N-desmethyl imatinib was delayed 35.70%,C_(max) of N-desmethyl imatinib was decreased by 20.01% and the Vz/F was increased by 45.38%,CL/F of N-desmethyl imatinib was increased by 32.44%.Conclusion The study shows that Xiaoaiping may affect the metabolism of imatinib both in vitro and vivo.When imatinib was co-administrated with Xiaoaiping,attention should be paid to clinical symptoms and Tmaxof imatinib.
Objective To investigate the effect of Chinese medicine Xiaoaiping on metabolism of imatinib in vitro and in vivo.Methods Incubation system of human and rat liver microsomes were added with 2.0μl Xiaoaiping injection or 10 times diluted Xiaoaiping injection,respectively.The amount of N-desmethyl imatinib was determined with UPLC-MS/MS when the reaction was terminated.Sixteen SD rats were randomly divided into control group and Xiaoaiping group with 8 in each group,7.5 ml/kg Xiaoaiping was intraperitoneally injected in Xiaoaiping group for 10 days.At d10 a single dose of 30 mg/kg imatinib was administered intragastrically in both groups,the blood samples were taken at 0.25,0.5,1,2,4,6,8,12 and 24 h after gavage for pharmacokinetic study.Results In vitro study showed that the inhibition rates of Xiaoaiping injection and 10 times diluted Xiaoaiping were 90.83% and 50.73% in rat liver microsomes,those were 79.44% and 28.77% in human liver microsomes.In vivo study showed that compared with control group,in Xiaoaiping group the Tmaxof imatinib was delayed 105.72%,the Vz/F was decreased by 24.76%,AUC_(0-t) of N-desmethyl imatinib was decreased by 21.37%,AUC_(0-∞) of N-desmethyl imatinib was decreased by 19.29%,Tmaxof N-desmethyl imatinib was delayed 35.70%,C_(max) of N-desmethyl imatinib was decreased by 20.01% and the Vz/F was increased by 45.38%,CL/F of N-desmethyl imatinib was increased by 32.44%.Conclusion The study shows that Xiaoaiping may affect the metabolism of imatinib both in vitro and vivo.When imatinib was co-administrated with Xiaoaiping,attention should be paid to clinical symptoms and Tmaxof imatinib.
引文
[1]于绍帅,陈明苍,李志雄,等.通关藤的化学成分与药理活性研究进展[J].中国实验方剂学杂志,2011,17(21):279-283.
[2]杨宗艳,胡传国.消癌平注射液治疗老年晚期非小细胞肺癌121例疗效观察[J].安徽医药,2010,14(12):1470-1471.
[3]贾军梅,赵和平,郭亚荣.消癌平联合奥曲肽对原发性肝癌患者免疫功能的影响[J].中国药物与临床,2011,11(10):1130-1132.
[4]傅柏涵,郭放,韩涛,等.消癌平注射液联合化疗治疗转移性三阴型乳腺癌临床疗效观察[J].解放军医药杂志,2016,28(6):23-26.
[5]周卫兵,何凤姣,姜武忠,等.消癌平联合同步放化疗治疗局部晚期鼻咽癌的临床观察[J].临床肿瘤学杂志,2009,14(11):1029-1031.
[6]李妮,冉建波.消癌平联合CPT-11化疗方案治疗老年晚期胃癌的临床疗效观察[J].河北医学,2016,22(2):198-201.
[7]董平.消癌平注射液联合CIK细胞治疗老年多发性骨髓瘤临床观察[J].中医学报,2015,30(12):1712-1717.DOI:10.16368/j.issn.1674-8999.2015.12.592.
[8]佟丽,董军杰,王茂生,等.消癌平注射液联合化疗治疗初发非M3型急性髓细胞白血病60例临床观察[J].河北中医,2015,37(1):95-97.
[9]刘宏明,张叶,宋滨.中药注射剂产生不良反应的原因分析及应对策略探讨[J].药学研究,2016,35(7):431-434.DOI:10.13506/j.cnki.jp r.2016.07.019.
[10]张师,王明霞,冯章英,等.靶向抗肿瘤药物的药动学相互作用研究进展[J].中国药房,2016,27(20):2871-2874.
[11]杨旭平,赖丹,黄毅岚.5种抗肿瘤中药注射液对CYP3A4酶代谢的影响[J].华西药学杂志,2014,29(5):550-552.DOI:10.13375/j.cnki.wc jp s.2014.05.022.
[12]刘丽雅,韩永龙,余奇,等.消癌平注射液等4种抗肿瘤中药注射剂对人肝微粒体中CYP450酶7种亚型的体外抑制作用研究[J].中国临床药理学与治疗学,2014,19(5):522-527.
[13]周静雅.抗肿瘤药物体内测定方法及与消癌平注射液的相互作用研究[D].上海:第二军医大学,2012.
[14]徐泽宽,徐皓.甲磺酸伊马替尼血药浓度监测对指导胃肠间质瘤治疗及评估预后临床意义[J].中国实用外科杂志,2015,35(4):387-390.
[15]刘晓蕾,姚海英,刘永建.伊马替尼治疗慢性粒细胞白血病期间谷浓度与疗效的关系[J].中国现代医学杂志,2012,22(10):42-44.
[16]国家药典委员会.中华人民共和国药典临床用药须知化学药和生物制品卷[M].北京:中国医药科技出版社,2011:945-947.
[2]杨宗艳,胡传国.消癌平注射液治疗老年晚期非小细胞肺癌121例疗效观察[J].安徽医药,2010,14(12):1470-1471.
[3]贾军梅,赵和平,郭亚荣.消癌平联合奥曲肽对原发性肝癌患者免疫功能的影响[J].中国药物与临床,2011,11(10):1130-1132.
[4]傅柏涵,郭放,韩涛,等.消癌平注射液联合化疗治疗转移性三阴型乳腺癌临床疗效观察[J].解放军医药杂志,2016,28(6):23-26.
[5]周卫兵,何凤姣,姜武忠,等.消癌平联合同步放化疗治疗局部晚期鼻咽癌的临床观察[J].临床肿瘤学杂志,2009,14(11):1029-1031.
[6]李妮,冉建波.消癌平联合CPT-11化疗方案治疗老年晚期胃癌的临床疗效观察[J].河北医学,2016,22(2):198-201.
[7]董平.消癌平注射液联合CIK细胞治疗老年多发性骨髓瘤临床观察[J].中医学报,2015,30(12):1712-1717.DOI:10.16368/j.issn.1674-8999.2015.12.592.
[8]佟丽,董军杰,王茂生,等.消癌平注射液联合化疗治疗初发非M3型急性髓细胞白血病60例临床观察[J].河北中医,2015,37(1):95-97.
[9]刘宏明,张叶,宋滨.中药注射剂产生不良反应的原因分析及应对策略探讨[J].药学研究,2016,35(7):431-434.DOI:10.13506/j.cnki.jp r.2016.07.019.
[10]张师,王明霞,冯章英,等.靶向抗肿瘤药物的药动学相互作用研究进展[J].中国药房,2016,27(20):2871-2874.
[11]杨旭平,赖丹,黄毅岚.5种抗肿瘤中药注射液对CYP3A4酶代谢的影响[J].华西药学杂志,2014,29(5):550-552.DOI:10.13375/j.cnki.wc jp s.2014.05.022.
[12]刘丽雅,韩永龙,余奇,等.消癌平注射液等4种抗肿瘤中药注射剂对人肝微粒体中CYP450酶7种亚型的体外抑制作用研究[J].中国临床药理学与治疗学,2014,19(5):522-527.
[13]周静雅.抗肿瘤药物体内测定方法及与消癌平注射液的相互作用研究[D].上海:第二军医大学,2012.
[14]徐泽宽,徐皓.甲磺酸伊马替尼血药浓度监测对指导胃肠间质瘤治疗及评估预后临床意义[J].中国实用外科杂志,2015,35(4):387-390.
[15]刘晓蕾,姚海英,刘永建.伊马替尼治疗慢性粒细胞白血病期间谷浓度与疗效的关系[J].中国现代医学杂志,2012,22(10):42-44.
[16]国家药典委员会.中华人民共和国药典临床用药须知化学药和生物制品卷[M].北京:中国医药科技出版社,2011:945-947.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |