目的 建立测定大鼠血浆中F1含量的LC-MS/MS方法,研究F1在大鼠体内的药动学和生物利用度。方法 大鼠分别经灌胃(10 mg·kg-1)、静脉注射(5 mg·kg-1)给药后,运用所建立的LC-MS/MS测定其血药浓度,选用DAS2.0软件求算药动学参数,根据灌胃、静脉注射给药药-时曲线下面积和给药剂量,计算F1的绝对生物利用度。结果 灌胃和静脉注射后ACU0-t分别为(27.052±10.068)和(153.878±88.777)ng·h·mL-1; AUC0-∞分别为(31.425±9.261)和(179.054±116.794)ng·h·mL-1; MRT0-t分别为(10.722±4.335)和(2.398±1.344)h; MRT0-∞分别为(15.651±5.917)和(6.925±7.013)h; t1/2分别为(4.294±1.534)和(6.052±3.633)h; ρmax分别为(18.394±17.856)和(219.079±142.207)ng·mL-1。 F1在大鼠体内的绝对生物利用度为8.79%。结论 建立了可用于测定大鼠血浆中F1的含量的方法,实验结果能指导F1进行结构优化,改善F1在体内的药动学特性,为提高F1的生物利用度提供实验依据。
Abstract
OBJECTIVE To establish a LC-MS/MS method for determining F1 in rat plasma and study the pharmacokinetic properties of F1. METHODS Ten healthy SD rats were enrolled in this study. They were randomly divided into two groups and received intragastric(10 mg·kg-1) and intravenous administration(5 mg·kg-1) of F1. After receiving F1, the concentrations of F1 in plasma were determined. Blood samples(0.1 mL)were immediately collected into heparinized tubes before injection and at 0,0.08, 0.25,0.5,0.75,1,2,4,6,8,10,12,24 h after injection. The pharmacokinetic parameters were determined by DAS2.0 software, absolute bioavailability of F1 was calculated based on AUC and dose administered. RESULTS The main pharmacokinetic parameters after intragastric and intravenous administration of F1 were as follows: ACU0-t(27.052±10.068),(153.878±88.777)ng·h·mL-1;AUC0-∞(31.425±9.261),(179.054±116.794)ng·h·mL-1;MRT0-t(10.722±4.335), (2.398±1.344)h; MRT0-∞ (15.651±5.917),(6.925±7.013)h;t1/2(4.294±1.534),(6.052±3.633)h;ρmax(18.394±17.856),(219.079±142.207)ng·mL-1,respectively. Absolute bioavailability value was 8.79%. CONCLUSION This method can be used to determine the content of F1 in rat plasma. The experimental results can guide the structural optimization of F1, improve the pharmacokinetics of F1 in vivo and provide experimental basis for improving bioavailability of F1.
关键词
LC-MS/MS /
F1 /
药动学 /
组蛋白去乙酰化酶抑制剂 /
绝对生物利用度
{{custom_keyword}} /
Key words
LC-MS/MS /
F1 /
pharmacokinetics /
histone deacetylase inhibitor absolute bioavailability
{{custom_keyword}} /
中图分类号：
R969.1
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] TAN Y M,WANG W Y,YU N F. Structure-activity relationships of histone deacetylase inhibitors[J]. Acta Pharm Sin(药学学报),2009,44(10):1072-1074.
[2] PETRUCCELLI L A, PETTERSSON F, DEL RINCON S V,et al. Expression of leukemia associated fusion proteins increases sensitivity to histone deacetylase inhibitor induced DNA damage and apoptosis[J]. Mol Cancer Ther,2013,12(8):1591-1593.
[3] WU L. Research on the synthesis of hydroxamic acids histone deacetylase inhibitor N25 and its anti-tumor effect in vitro[D]. Guangzhou: Guangdong University of Pharm (广东药学院),2013.
[4] PANG C H, WANG D Y. Synthesis,characterization and preliminary anti-tumor activities of the novel Schiff bases containing hydroxamic acid group[J]. Guangdong Chem Ind(广东化工),2016, 43(20):24-25.
[5] HE D, MA S X, GUO Q X,et al. Synthesis of benzene substituted hydroxyl acids as histone deacetylase inhibitors and evaluation of antitumor activity in vitro[J]. Chin New Drugs J(中国新药杂志),2014,23(12):1439-1442.
[6] KELLY W K,RICHON V M,O'CONNOR O,et al. Phase I clinical trial of histone deacetylase inhibitor suberoylanilide hydroxamic acid administered intravenously[J]. Clin Cancer Res,2003,9(10):3578-3588.
[7] ZENG W, ZENG G Y, QIN S Y. Recent advances in the synthesis and application of hydroxamic acid[J]. Chin J Org Chem(有机化学),2003,23(11):1213-1216.
[8] BEHERA J, JAYPRAKASH V, NAYAN SINHA B. Histone deacetylase Inhibitors:a review class-Ⅰspecific inhibition[J]. Mini Re Med Chem,2015,15(20):731-733.
[9] ZHANG H L, LI H J, WANG Q H. Mechanisms of histone deacetylase inhibitor in treating T-cell lymphoma and related clinical trials[J]. Chin J Clin Oncol(中国肿瘤临床),2014,41(19):1213-1215.
[10] ZHANG L K, WANG X Z, LI W S, et al. Pharmacokinetic and bioavailability study of curcumin in rats[J]. Chin Pharm Bull(中国药理报通报),2011,27(10):1460-1461.
[11] FENG X J,WANG M X,FENG Z Y. Pharmacokinetic study of matrine injection in rats with different administration ration routes by LC-MS/MS method[J]. Chin Pharm J(中国药学杂志),2017, 52(4):305-307.
[12] YANG K Y,LIN L C,TSENG T Y, et al. Oral bioavailability of curcum in rat and the herbal analysis from curcuma longa by LC-MS/MS[J]. J Chromatogr B,2007,853(1-2):183-189.
[13] LI J, WANG G J. Intestinal absorption barrier and novel strategies for absorption enhancement[J]. Acta Pharm Sin(药学学报),2005,40(7):600-605.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
四川省创新团队项目资助(15TD0011)
{{custom_fund}}
PDF(1267 KB)
