人体中伊曲康唑及其活性代谢产物羟基伊曲康唑的整合药代动力学研究

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (1): 56-63.

人体中伊曲康唑及其活性代谢产物羟基伊曲康唑的整合药代动力学研究

付淑军^1,2, 冯利民³, 孙连福⁴, 刘昌孝¹, 何新¹

¹天津中医药大学中药学院,天津 300193;
²瀚盟生物技术(天津)有限公司,天津 300457;
³天津中医药大学第二附属医院,天津 300150;
⁴石药集团中奇制药技术(石家庄)有限公司,石家庄 050051,河北

收稿日期:2014-02-22 修回日期:2014-06-23 发布日期:2020-07-20
通讯作者: 何新,通信作者,女,教授,博士生导师,主要研究方向:药物代谢动力学。Tel:022-59596231 E-mail:hexintn@163.com
作者简介:付淑军,女,硕士,研究方向:药物代谢动力学。Tel:15122485925 E-mail:fushujun90@aliyun.com
基金资助:
天津市自然科学基金重点项目(12JCZDJC26100);教育部“创新团队发展计划(IRT-14R41)

Integrated pharmacokinetic study of itraconazole and its active metabolite-hydroxyitraconazole in human

FU Shu-jun^1,2, FENG Li-min³, SUN Lian-fu⁴, LIU Chang-xiao¹, HE Xin¹

¹Faculty of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China;
²Hanmonia Biotechnology(Tianjin) Limited Company, Tianjin 300457, China;
³The Second Affiliated Hospital of Tianjin University of TCM, Tianjin 300150, China;
⁴Shijiazhuang Pharm Group, Zhong Qi Pharmaceutical Technology (Shijiazhuang) co., Ltd, Shijiazhuang 050051, Hebei, China

Received:2014-02-22 Revised:2014-06-23 Published:2020-07-20

摘要/Abstract

摘要： 目的: 羟基伊曲康唑(OH-ITZ)为目前临床一线抗真菌药伊曲康唑(ITZ)的主要活性代谢产物,其与ITZ有着相似的抗菌活性,且血药浓度较母体药物高,因此OH-ITZ的体内过程对临床疗效的影响研究不容忽视。本文旨在建立灵敏、快速的液相色谱-串联质谱法同时测定人血浆中ITZ及OH-ITZ,并应用整合药代动力学模型进行整体评价。方法: 血浆样品经沉淀蛋白后,以乙腈(甲酸 0.1%)-水(甲酸 0.1%)为流动相梯度洗脱,Zorbax XDB C₁₈柱分离,采用电喷雾电离源,以多反应监测(MRM)方式进行正离子检测。定量分析所用的离子反应分别为m/z 705 →m/z 392(ITZ),m/z 721→m/z 408(OH-ITZ)和m/z 386→m/z 122(内标,丁螺环酮)。结果: 测定血浆中ITZ及OH-ITZ的线性范围均为 0.50~500 ng/mL,日内、日间精密度(RSD)均小于 12.4%,准确度(RE)均在±7.5%以内;整合药动学研究结果显示综合浓度药-时曲线符合口服给药药物消除规律,整合后主要药动学参数t_1/2和AUC_0-∞分别为 19.5 h,5754 ng·h·mL^-1。结论: 本方法运行时间短、选择性强、灵敏度高、操作简便、血浆用量少,适用于ITZ及OH-ITZ的临床药代动力学研究;其整合药动学模型研究所获参数能够表征ITZ和OH-ITZ的整体处置规律,符合经典药代动力学模型特征。

关键词: 伊曲康唑(ITZ), 羟基伊曲康唑(OH-ITZ), 液相色谱-串联质谱法, 整合药代动力学

Abstract: AIM: Hydroxyitraconazole (OH-ITZ) is the magor active metabolite of itraconazole (ITZ) which is the first-line antifungal drug and it has antifungal activity similar to ITZ. Forther more, the plasma concentration of OH-ITZ is higher than that of ITZ. Therefore, it can not be ignored that the pharmacokinetics of OH-ITZ effect on the clinical therapeutic effects. This study was designed to develop a sensitive and rapid LC-MS/MS method for direct determination of ITZ and OH-ITZ in human plasma and to study the integrated pharmacokinetics of ITZ and OH-ITZ in human. METHODS: ITZ, OH-ITZ andinternal standard (buspirone) were pretreated from plasma OH-ITZ in human using protein precipitation with acetonitrile/methanol(1∶1). Chromatographic separation was achieved on an Agilent Zorbax-C₁₈ column (2.1 mm×50 mm, 3.5 μm) using a step gradient program with the mobile phase of 0.1% formic acid aqueous solution and acetonitrile with 0.1% formic acid, at a flow-rate of 0.50 mL/min. Electrospray ionization (ESI) source was applied and operated in the positive ion mode. Multiple reaction monitoring (MRM) mode with the transitions of m/z 705 →m/z 392, m/z 721→m/z 408 and m/z 386→m/z 122 was performed to quantify ITZ, OH-ITZ and IS, respectively. RESULTS: The linear concentration ranges of calibration curves for ITZ and OH-ITZ were 0.50-500 ng/mL. The inter- or intra-day precision (RSD) was less than 12.4% and the accuracy (RE) was within±7.5%. Based on the AUC weighting coefficients integration approach, the integrated pharmacokinetic parameters were calculated. The holistic t_1/2 and AUC_0-∞ were of 19.5 hr and 5754 ng·h·mL^-1 in human plasma after oral administration of 200 mg itraconazole. CONCLUSION: The method is sensitive, rapid, convenient, using less plasma and is proved to be suitable for clinical pharmocokinetics of ITZ and OH-ITZ. The holistic pharmacokinetic properties of ITZ and OH-ITZ were described successfully.

Key words: itraconazole(ITZ), hydroxyitraconazole(OH-ITZ), liquid chromatography-tandem mass spectrometry, integrated pharmacokinetics

中图分类号:

R969

付淑军, 冯利民, 孙连福, 刘昌孝, 何新. 人体中伊曲康唑及其活性代谢产物羟基伊曲康唑的整合药代动力学研究[J]. 中国临床药理学与治疗学, 2015, 20(1): 56-63.

FU Shu-jun, FENG Li-min, SUN Lian-fu, LIU Chang-xiao, HE Xin. Integrated pharmacokinetic study of itraconazole and its active metabolite-hydroxyitraconazole in human[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(1): 56-63.

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