当前位置:
首页
网刊
UPLC-MS/MS研究抗肿瘤化合物HK-7在不同种属肝微粒体中的代谢稳定性和代谢酶表型
UPLC-MS/MS研究抗肿瘤化合物HK-7在不同种属肝微粒体中的代谢稳定性和代谢酶表型
夏媛媛1,2,杨沮勤1,2,朱伊婷1,2,陈英杰1,2,汤明海2,万 丽1

1 成都中医药大学药学院,成都 611137;2 四川大学华西医院生物治疗国家重点实验室,成都 610041
Investigation of metabolic stability and metabolic enzyme phaenotypes of anti-tumor compound HK-7 in different species of liver microsomes by UPLC-MS/MS
(1 School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China;2 State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041,China)

摘要参考文献相关文章

起始页:178

摘要:[摘要] 目的:应用体外肝微粒体孵育体系,研究抗肿瘤化合物HK-7在人、SD大鼠、昆明种小鼠、恒河猴和比格犬的肝微粒体中的代谢稳定性,确定HK-7在人肝微粒体中的代谢表型。方法:通过UPLC-MS/MS检测方法,测定在各个种属中孵育后的HK-7剩余浓度,考察它们的代谢稳定性及体外代谢动力学参数。采用化学抑制剂法预测HK-7在人肝微粒体中的代谢表型。结果:在人、SD大鼠、昆明种小鼠、恒河猴和比格犬的肝微粒体中,HK-7的体外代谢半衰期t 1/2分别为44.91,83.42,72.70,48.93和66.21 min;体外固有清除率CLint分别为0.031,0.016,0.019,0.028和0.021 mL?min-1?mg-1;在人肝微粒体中HK-7主要被细胞色素CYP2C9, CYP2E1和CYP3A4催化代谢。结论:HK-7在肝微粒体中的代谢存在种属差异,人肝微粒体中参与HK-7代谢的酶可能有CYP2C9, CYP2E1和CYP3A4,其中CYP2E1贡献最大。

关键词:[关键词] HK-7;代谢稳定性;肝微粒体;代谢表型

通讯作者:

基金项目:

作者简介:

Abstract:
[Abstract] Objective: To investigate the metabolic stability of HK-7 in liver microsomes of human, SD rats, Kunming mice, Rhesus ms and Beagle dogs, and identify the main enzymes involved in HK-7 metabolism in human liver microsomes. Methods: After being incubated with different species of liver microsomes, HK-7 was quantified by UPLC-MS/MS method to evaluate its stability and metabolic kinetic parameters in vitro. The CYP450 phenotype of HK-7 was identified by specific inhibitors of isoforms in human microsomal incubation system. Results: The in vitro half-lives (t1/2) of HK-7 in liver microsomes of human, SD rats, Kunming mice, Rhesus ms and Beagle dogs were 44.91,83.42,72.70,48.93,and 66.21 min respectively. Their intrinsic clearance rates (CLint) were 0.031, 0.016, 0.019, 0.028, and 0.021 mL?min-1?mg-1, respectively. CYP2C9, CYP2E1, and CYP3A4 were found to be the major CYP isoforms involved in HK-7 metabolism. Conclusion: There is significant difference in the metabolic rate of HK-7 between different species. The metabolism of HK-7 in human liver microsomes may be CYP2C9, CYP2E1 and CYP3A4, and CYP2E1 has the greatest contribution to its metabolism.

Key words:[Key words] HK-7;metabolicstability;liver microsomes;metabolic phenotyping

    [1] 国家药典委员会.中华人民共和国药典[S]. 2015年版一部.北京:中国医药科技出版社,2015:251.
    [2] 张淑洁, 钟凌云. 厚朴化学成分及其现代药理研究进展[J].中药材, 2013, 36(5): 838-841.
    [3] 林晓辉,张雪原,朱吉士,等. HPLC法测定脾约丸中厚朴酚与和厚朴酚的含量

    [J]. 今日药学,2015,25(2):114-115,119.
    [4] LI Z, LIU Y, ZHAO X, et al. Honokiol, a natural therapeutic candidate, induces apoptosisand inhibits angiogenesis of ovarian tumor cells[J]. Eur J Obstet Gynecol Reprod Biol, 2008, 140(1): 95-102.
    [5] LUO Y, XU Y, CHEN L, et al. Preparative purification of anti-tumor derivatives of honokiol by high-speed counter-current chromatography[J]. J Chromatogr A, 2008, 1178(1-2): 160-165.
    [6] 吴慧,彭英,孙建国,等.体外代谢在新药早期评价中的应用与发展[J].药学学报, 2013, 48(7): 1071-1079.
    [7] WANG P, ZHAO Y, ZHU Y, et al. Metabolism of dictamnine in liver microsomes from mouse, rat, dog, monkey, and human[J]. J Pharm Biomed Anal, 2016, 119: 166-174.
    [8] TANG X, DI X, ZHONG Z, et al. In vitro metabolism of L-corydalmine, a potent analgesic drug, in human, cynomolgus monkey, beagle dog, rat and mouse liver microsome[J]. J Pharm Biomed Anal, 2016, 128: 98-105. 
    [9] 袁春平, 侯惠民, 曾杉. 丹酚酸B及二甲酯在人肝微粒体中代谢稳定性研究及代谢产物鉴定[J].中国新药杂志, 2016, 25(13): 1543-1549.
    [10] 张剑萍,郭澄.生物样品分析中的方法学验证[J].中国药房,2008,19(31): 2469.
    [11] 杨然,马晓慧,郭嘉华, 等. 药物代谢酶的特性[J]. 中国新药杂志, 2016,25(7):741-758.