南北五味子提取物对大鼠体内环磷酰胺代谢的影响

冯格, 翟健秀, 陈万生, 熊筱娟, 高守红, 夏天一, 张凤

中国医院药学杂志 ›› 2018, Vol. 38 ›› Issue (1) : 30-35,40.

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中国医院药学杂志 ›› 2018, Vol. 38 ›› Issue (1) : 30-35,40. DOI: 10.13286/j.cnki.chinhosppharmacyj.2018.01.08
研究论文

南北五味子提取物对大鼠体内环磷酰胺代谢的影响

  • 冯格1,2, 翟健秀1,3, 陈万生1, 熊筱娟2, 高守红1, 夏天一1, 张凤1
作者信息 +

Effects of Wuzhi capsules and Schisandrae chinensis fructus extract on cyclophosphamide metabolism in rats

  • FENG Ge1,2, ZHAI Jian-xiu1,3, CHEN Wan-sheng1, XIONG Xiao-juan2, GAO Shou-hong1, XIA Tian-yi1, ZHANG Feng1
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摘要

目的:探讨南北五味子提取物分别对环磷酰胺(CTX)及其代谢产物羧基磷酰胺(CPM)、4-酮基环磷酰胺(4-Keto CTX)、脱氯乙基环磷酰胺(DC-CTX)血浆药动学及尿排泄的影响,从药物相互作用影响环磷酰胺代谢的角度阐明南北五味子的减毒作用机制。方法:采用UHPLC-MS/MS法同时测定大鼠血浆或尿液中CTX及其代谢产物的浓度。将SD大鼠随机分组分别给药分别取样,采集不同时间点血浆样品,绘制药-时曲线,并用DAS2.0软件一室模型拟合药动学参数,使用单因素方差分析法比较组间药动学参数的差异性;采集不同时间段尿液样本,计算待测成分的累积排泄量。结果:CTX单独给药组、合并南五味子提取物(制剂五酯胶囊,WZC,300 mg·kg-1)给药组,以及合并北五味子醇提物(BWWZ,750 mg·kg-1)给药组,不同待测物的AUC(μg·h-1·mL-1)分别为:CTX:411.818±82.10,483.492±174.49,683.92±91.70;DC-CTX:683.97±91.70,35.95±70.51,8.44±3.96;4-Keto CTX:87.27±38.81,25.78±10.03,17.18±37.2;CPM:99.74±16.18,110.21±57.99,104.90±16.23。Cmaxμg·mL-1)分别为:CTX:233.41±32.10,255.021±45.90,249.27±17.52;DC-CTX:3.63±1.25,1.21±13.48,1.31±0.72;4-Keto CTX:5.24±1.04,5.34±2.41,2.84±0.81;CPM:25.88±5.26,27.53±8.11,22.42±4.75。48 h内的累积排泄量(μg)分别为:CTX:1 455.36,3 829.16,4 830.69;DC-CTX:2 136.21,921.18,468.87;4-Keto CTX:759.18,1 348.54,338.38;CPM:9 268.06,17 386.18,8 902.05。结论:WZC和BWWZ对CTX的代谢产物DC-CTX的药动学及尿液排泄均有显著影响,均可通过抑制CYP3A4活性使得侧链代谢毒性产物氯乙醛的生成明显降低;结合血浆、尿液中的实验结果可知在血浆中浓度较高的待测物在尿液中排泄也较多,使用WZC和BWWZ均可促进CTX原型和CPM的排泄。

Abstract

OBJECTIVE To discuss the effects of Wuzhi capsules (WZC) and Schisandrae chinensis fructus extract (BWWZ) on the pharmacokinetics and urinary excretion behaviors of cyclophosphamide (CTX) as well as its metabolites carboxyl phosphoramide (CPM), 4-Keto cyclophosphamide (4-Keto CTX) as well as dechlorination ethyl cyclophosphamide (DC-CTX), and to illustrate the mechanism of toxicity attenuation effects of WZC and BWWZ by exploring their interactions with CTX metabolism.METHODS A valid UHPLC-MS/MS method was applied for simultaneous determination of CTX as well as its metabolites in rat plasma and urine. The Sprague Dawley rats were randomly divided into three groups (CTX group; BWWZ group, 750 mg·kg-1; WZC group, 300 mg·kg-1) and plasma samples were collected at different time points using an orbital sampling method. The concentration time curve was constructed using a DAS2.0 software for calculation of the pharmacokinetic parameters by one-compartment model. The pharmacokinetic parameters from different groups were compared by one-way ANOVA for significance analysis. In addition, urine samples were gained from different time periods to obtain the total cumulative excretion.RESULTS The areas under the curve (AUC,μg·h·mL-1) of the analytes were 411.818±82.10, 483.492±174.49 and 683.92±91.70 for CTX; 683.97±91.70, 35.95±70.51 and 8.44±3.96 for DC-CTX; 87.27±38.81, 25.78±10.03 and 17.18±37.2 for 4-Keto CTX; 99.74±16.18, 110.21±57.99 and 104.90±16.23 for CPM in CTX, WZC and BWWZ groups, respectively. Maximum plasma concentrations (Cmax,μg·mL-1) of the analytes were 233.41±32.10, 255.021±45.90 and 249.27±17.52 for CTX; 3.63±1.25, 1.21±13.48 and 1.31±0.72 for DC-CTX; 5.24±1.04, 5.34±2.41 and 2.84±0.81 for 4-Keto CTX; 25.88±5.26, 27.53±8.11 and 22.42±4.75 for CPM in CTX, WZC and BWWZ groups. The 48 h urinary cumulative excretions(μg) were 1 455.36, 3 829.16 and 4 830.69 for CTX; 2 136.21, 921.18 and 468.87 for DC-CTX; 759.18, 1 348.54 and 338.38 for 4-Keto CTX; 9 268.06, 17 386.18 and 8 902.05 for CPM in CTX, WZC and BWWZ groups.CONCLUSION Both WZC and BWWZ can influence the pharmacokinetic behaviors of DC-CTX which results in the reduction of the toxic metabolite chloroacetaldehyde, as a consequence of CYP3A4 inhibition. It can be observed from the experiment that the rich abundance of the analyte in plasma, the greater the urinary excretion. Both WZC and BWWZ can accelerate the excretion of CTX and CPM.

关键词

五酯胶囊 / 北五味子提取物 / 环磷酰胺 / 药物相互作用 / 药动学 / 尿排泄

Key words

Wuzhi capsules / Schisandrae chinensis fructus / cyclophosphamide / drug interactions / pharmacokinetics / excretion

引用本文

导出引用
冯格, 翟健秀, 陈万生, 熊筱娟, 高守红, 夏天一, 张凤. 南北五味子提取物对大鼠体内环磷酰胺代谢的影响[J]. 中国医院药学杂志, 2018, 38(1): 30-35,40 https://doi.org/10.13286/j.cnki.chinhosppharmacyj.2018.01.08
FENG Ge, ZHAI Jian-xiu, CHEN Wan-sheng, XIONG Xiao-juan, GAO Shou-hong, XIA Tian-yi, ZHANG Feng. Effects of Wuzhi capsules and Schisandrae chinensis fructus extract on cyclophosphamide metabolism in rats[J]. Chinese Journal of Hospital Pharmacy, 2018, 38(1): 30-35,40 https://doi.org/10.13286/j.cnki.chinhosppharmacyj.2018.01.08
中图分类号: R932   

参考文献

[1] Ch.P (2015)Vol Ⅰ(中国药典2015年版一部)[S].2015:244-245, 66-67.
[2] Wei H.Studies onthe pharmacokinetics of Wuzhicapsuleand interactionsof tacrolimusand Wuzhi capsule[D].Second Military Medical University (第二军医大学), 2010.
[3] Wu XC, XinHw, LiX, et al. The pharmacokinetic effects 0f Wuzhi capsule to healthy subjects for Midazolam and (1'-hydroxymidazolam[J].Chin J Clin Pharmacol Ther(中国临床药理学与治疗学), 2009, 14(3):313-317.
[4] Wei H, Tao X, Di P, et al. Effects of traditional chinese medicine Wuzhi capsule on pharmacokinetics of tacrolimus in rats[J]. Drug Metab Dispos, 2013, 41(7):1398-1403.
[5] Kong LH, Y L, Duan HJ. The function composition analysis of Fructusschisandrae alcohol extract on the liver[J].Academic J PLA Pharma Sci(解放军药学学报), 2010, 26(1):27-31.
[6] Yu Q.The effects of different extracts offruit of Chinese magnoliavine on lipid metabolism in mice were studied[D].Beijing University of Traditional Chinese Medicine (北京中医药大学), 2013.
[7] Yin FZ, LiL, ZX, et al.Quality analysis on the lignans from the processed of FructusSchisandraechinensis[J].Chin Hosp Pharm J (中国医院药学杂志), 2013, 33(12):928-931.
[8] Hundemer M, Engelhardt M, Bruckner T, et al. Rescue stem cell mobilization with plerixafor economizes leukapheresis in patients with multiple myeloma[J]. J Clin Apher, 2014, 29(6):299-304.
[9] Jonge DMED, Huitema ADR, Rodenhuis S, et al. Clinical pharmacokinetics of cyclophosphamide[J]. Clin Pharmacokinet, 1991, 20(3):194-208.
[10] de Jonge ME, Huitema ADR, van Dam SM, et al. Significant induction of cyclophosphamide and thiotepa metabolism by phenytoin[J]. Cancer Chemother Pharmacol, 2005, 55(5): 507-510.
[11] Yang L. Studies on UHPLC-MS/MS method determination of commonanticancer drugs and study about the interaction betweencyclophosphamide and ketoconazole[D].Second Military Medical University(第二军医大学), 2014.
[12] Chen L,Gao SH,Xiong XJ,et al. Simultaneous quantitation of cyclophosphamide and its metabolites in rat plasma using UHPLC-MS/MS[J]. Acad J Sec Milit Med Univ(第二军医大学学报), 2016, 37(9):29-35.
[13] Ke XH, Li H, Su JC,et al. Comparason for lignan content in schisandraesphenantherae fructus and schisandrae chinensis fructus[J]. Chin J Exper Trad Med Formulae (中国实验方剂学杂志), 2015, (17): 40-43.
[14] Wei H, Sun LN, Tai ZG, et al. A simple and sensitive HPLC method for the simultaneous determination of eight bioactive components and fingerprint analysis of Schis and rasphenanthera[J].Analytica Chimica Acta, 2010, 662(1): 97-104.
[15] ZY H, YD L.Research progress on pharmacology of cyclophosphamide[C].China Meeting (中国会议), 2008: 466-470.
[16] Feng G, Zhai JX, Chen WS, et al.Study on the interaction between the Schisandra chinensis and Schisandra sphenanthera as well as its preparations with other drugs[J].Chin Hosp Pharm J(中国医院药学杂志),2017, 37(21):2206-2209.

基金

国家自然科学基金资助项目(编号:81573793);上海市临床药学重点专科建设项目(编号:2016-40044-002)

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