LC/MS/MS法测定比格犬血浆中埃克替尼及其在药动学研究中的应用

中国临床药理学与治疗学 ›› 2008, Vol. 13 ›› Issue (10): 1158-1162.

LC/MS/MS法测定比格犬血浆中埃克替尼及其在药动学研究中的应用

关忠民¹, 陈笑艳², 钟大放^1,2, 王印祥³

¹沈阳药科大学, 沈阳 110016, 辽宁;
²中国科学院上海药物研究所, 上海 201203;
³浙江贝达药业, 杭州 310004, 浙江

收稿日期:2008-05-28 修回日期:2008-10-16 出版日期:2008-10-26 发布日期:2020-10-19
作者简介:关忠民, 男, 博士研究生, 研究方向:药物代谢与药物动力学。

Pharmacokinetics of icotinib in Beagle dog studied by using LC/MS/MS method

GUAN Zhong-min¹, CHEN Xiao-yan², ZHONG Da-fang^1,2, WANG Yin-xiang³

¹Shenyang Pharmaceutical University, Shenyang110016, Liaoning, China;
²Shanghai Institute of Materia Medi-ca, Chinese Academy of Sciences, Shanghai 201203, China;
³Zhejiang Beta Pharma Inc ., Hangzhou 310004,Zhejiang, China

Received:2008-05-28 Revised:2008-10-16 Online:2008-10-26 Published:2020-10-19

摘要/Abstract

摘要： 目的: 建立灵敏、快速的液相色谱-串联质谱(LC/MS/MS) 法测定比格犬血浆中埃克替尼, 并用于药动学研究。方法: 健康比格犬 32 只, 随机分成 4 组后, 静脉(10 mg/kg) 或灌胃(10, 20 和40 mg/kg) 给予埃克替尼。采用 LC/MS/MS 法测定血药浓度, 并计算出药动学参数。结果: 测定埃克替尼的线性范围是 0.5 ~ 10000 ng/mL, 日内和日间精密度(RSD) 均小于 10 %。静脉给药后 AUC_0-t为(27.3±15.3) μg^。mL^-1。h。灌胃给药后 AUC_0-t分别为(7.47 ±3.30) 、(23.5 ±11.5) 、(54.5 ±24.9) μg^。mL^-1。h, 埃克替尼在犬体内的绝对生物利用度是 27.4%。结论: 该分析方法选择性好、灵敏度高、操作简便, 并成功应用于埃克替尼的比格犬药动学研究。

关键词: 埃克替尼, 药动学, LC/MS/MS 法, 比格犬

Abstract: AIM: To develop an LC/MS/MS meth-od for the determination of icotinib in dog plasma and study the pharmacokinetics of icotinib.METHODS: Icotinib was administered to 32 Beagle dogsvia intrave-nous bolus (10 mg/kg) or oral dosing (10, 20 or 40 mg/kg) administration after randomly dividing into 4 groups.The concentrations of icotinib in dog plasma were detected by using LC/MS/MS method, and the pharmacokinetic parameters were calculated.RESULTS: The linear calibration curves were obtained in the concentration range of 0.5 -10000 ng/mL .The relative standard deviation (RSD) of intra-day and in-ter-day was less than 10%.The value of area under the curve (AUC_0-t ) was (27.3 ±15.3) μg^。mL^-1。h after intravenous bolus administration.The values of AUC_0-t were (7.47 ±3.30) , (23.5 ±11.5) and (54.5 ±24.9) μg^。mL^-1。h after oral dosing for the three groups, respectively .The absolute bioavailability of icotinib in dog was 27.4%.CONCLUSION: The method is sensitive, selective and proved to be suitable for preclinical investigation of icotinib pharmacokinet-ics.

Key words: icotinib, pharmacokinetics, LC/MS/MS, Beagle dog

中图分类号:

R969.

关忠民, 陈笑艳, 钟大放, 王印祥. LC/MS/MS法测定比格犬血浆中埃克替尼及其在药动学研究中的应用[J]. 中国临床药理学与治疗学, 2008, 13(10): 1158-1162.

GUAN Zhong-min, CHEN Xiao-yan, ZHONG Da-fang, WANG Yin-xiang. Pharmacokinetics of icotinib in Beagle dog studied by using LC/MS/MS method[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(10): 1158-1162.

参考文献

[1] Wakeling AE, Guy SP, Woodburn JR, et al.ZD1839 (Iressa) :an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy[J] .Can-cer Res, 2002, 62(20) :5749-5754.
[2] Magne N, Fishel J, Dubreuil A, et al.Influence of epi-dermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antipro-liferative effect of ZD1839 (“ Iressa”)[J] .Br J Cancer,2002, 86(9) :1518-1523.
[3] O' Brien DP, Nelson LA, Williams JL, et al. Selective inhibition of the epidermal growth factor receptor impairs intestinal adaptation after small bowel resection[J] .J Surg Res, 2002, 105(1) :25-30.
[4] Pino MS, Shrader M, Baker CH, et al.Transforming growth factor alpha expression drives constitutive epider-mal growth factor receptor pathway activation and sensitiv-ity to gefitinib (Iressa) in human pancreatic cancer cell lines[J] .Cancer Res, 2006, 66(7) :3802-3812.
[5] Ciardiello F, TortoraG. A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor[J] .Clin Cancer Res, 2001, 7(10) :2958-2970.
[6] Zhang D, Xie GJ, Davis C, et al.International Publica-tion Number:WO 03 082830 A1.9October 2003.
[7] Anderson NG, Ahmad T, Chan K, et al.ZD1839 (Ires-sa) , a novel epidermalgrowth factor receptor (EGFR) ty-rosine kinase inhibitor, potently inhibits the growth of EG-FR-positive cancer cell lineswith or without erbB2 overex-pression[J] .Int J Cancer, 2001, 94(6) :774-782.
[8] McKillop D, Partridge EA, Hutchison M, et al. Pharma-cokinetics of gefitinib, anepidermalgrowth factor receptor tyrosine kinase inhibitor, in rat anddog[J] .Xenobiotica,2004, 34(10) :901-915.
[9] Meany HJ, Fox E, McCully C, et al. The plasma and ce-rebrospinal fluid pharmacokinetics of erlotinib and its ac-tive metabolite (OSI-420) after intravenous administra-tion of erlotinib in non-human primates[J] .Cancer Che-mother Pharmacol, 2008, 62(3) :387-392.
[10] Vermeer PD, Einwalter LA, Moninger TO, et al.Seg-regation of receptor and ligand regulates activation of epi-thelial growth factor receptor[J] .Nature, 2003, 422(6929) :322-326.

[1]	武玉洁, 赵程程, 席庆. 蒙特卡洛模拟评价替加环素治疗革兰阴性菌感染给药方案[J]. 中国临床药理学与治疗学, 2023, 28(9): 1027-1033.
[2]	黄志伟, 李熠, 徐晓勇, 张蕾, 沈一峰, 李华芳. 五种群体药动学分析工具计算结果的比较[J]. 中国临床药理学与治疗学, 2023, 28(5): 525-535.
[3]	燕强勇, 向大雄, 朱荣华, 杨玲凤, 阳喜定, 李晶晶, 范晓, 刘赛, 熊守军, 方平飞. 盐酸西那卡塞片在中国健康人群的生物等效性研究[J]. 中国临床药理学与治疗学, 2023, 28(2): 171-177.
[4]	刘璐, 石雨菲, 何庆烽, 徐凤艳, 王鲲, 蔡卫民, 相小强. 群体模型分析方法评估基因多态性对药物PK/PD的影响[J]. 中国临床药理学与治疗学, 2023, 28(11): 1275-1282.
[5]	李雪静, 江金平, 李思凝, 万林飞, 周响响, 杨梿, 兰轲. 一项在中国精神分裂症受试者中评估氯氮平片的生物等效性研究[J]. 中国临床药理学与治疗学, 2023, 28(10): 1121-1130.
[6]	张进华, 刘茂柏, 蔡铭智, 郑英丽, 劳海燕, 向倩, 都丽萍, 朱珠, 董婧, 左笑丛, 李新刚, 尚德为, 陈冰, 叶岩荣, 王玉珠, 高建军, 张健, 陈万生, 谢海棠, 焦正. 模型引导的华法林精准用药：中国专家共识（2022版）[J]. 中国临床药理学与治疗学, 2022, 27(11): 1201-1212.
[7]	贾元威, 沈杰, 储冀汝, 张翠锋, 谢海棠, 杨斌, 李相鸿, 郑丹丹, 赵静惠. 豆腐果苷及其代谢产物时辰药动学研究[J]. 中国临床药理学与治疗学, 2021, 26(9): 986-994.
[8]	徐国防, 高盼, 刘平, 赖耀文, 李广辉, 赵岳, 张永玲, 李晓苏, 齐琦. 肿瘤患者个体差异对卡培他滨药物代谢动力学影响[J]. 中国临床药理学与治疗学, 2021, 26(3): 305-311.
[9]	章思亮, 胡琳璘, 邵华, 陈西敬. 性别差异对精神药物作用影响的研究进展[J]. 中国临床药理学与治疗学, 2021, 26(3): 324-331.
[10]	张苗, 刘倩, 么雪婷, 刘东阳. 基于口服吸收生理药动学模型的创新药早期临床食物影响研究探索[J]. 中国临床药理学与治疗学, 2021, 26(12): 1426-1429.
[11]	焦正, 李新刚, 尚德为, 董婧, 左笑丛, 陈冰, 刘剑敏, 潘雁, 周田彦, 张菁, 刘东阳, 李禄金, 方翼, 马广立, 丁俊杰, 赵维, 陈锐, 相小强, 王玉珠, 高建军, 谢海棠, 胡蓓, 郑青山. 模型引导的精准用药：中国专家共识（2021版）[J]. 中国临床药理学与治疗学, 2021, 26(11): 1215-1228.
[12]	郭仙忠, 林荣芳, 林玮玮. 基于群体药动学模型的万古霉素个体化给药软件研制及应用[J]. 中国临床药理学与治疗学, 2021, 26(1): 30-39.
[13]	林忠, 谢群莉, 戴淑萍, 陈静, 林菲阳, 朱燕舞, 余国亮, 张远怀, 崔可. 中国成年患者利奈唑胺治疗群体药动学研究[J]. 中国临床药理学与治疗学, 2020, 25(9): 992-999.
[14]	向荣凤, 孙凤军, 熊丽蓉, 喻明洁, 戴青, 陈勇川. 左旋泮托拉唑钠肠溶片在健康人体内的药代动力学和药效学研究[J]. 中国临床药理学与治疗学, 2020, 25(8): 903-909.
[15]	李智慧, 刘静彦, 邱雯, 陈红. 氟康唑胶囊在中国健康受试者的人体生物等效性研究[J]. 中国临床药理学与治疗学, 2020, 25(8): 910-915.