二氢齐墩果酸甲酯的合成及其药动学与生物利用度研究  

Synthesis of methyl dihydrooleanolate and study of its pharmacokinetics and bioavailability

作　　者：李维[1] 李述敏[1] 李永[1] 杜克斯 范菊娣[1] 张吉泉[1] 汤磊[1] 

机构地区：[1]贵州医科大学,贵阳550004

出　　处：《中国新药杂志》2018年第3期351-355,共5页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(81703356);贵州省普通高等学校药物化学工程研究中心平台项目(黔教合KY字[2014]219号);贵州省化学合成药物研发利用工程技术研究中心平台项目(黔科合[2016]平台人才5402);贵州省科技支撑项目(黔科合[2016]支撑2819);贵州省卫计委科学技术基金项目(gzwjkj2016-1-051);贵州省联合基金资助项目(黔科合LH字[2015]7340;[2016]7349;[2016]7379)

摘　　要：目的:合成二氢齐墩果酸甲酯,并对其进行药动学与生物利用度评价。方法:以齐墩果酸为原料,经酯化、乙酰化、氧化、黄鸣龙还原及酯化等步骤得到二氢齐墩果酸甲酯;采用UPLC-QTOF液质联用测定大鼠血浆中的药物浓度,进行大鼠体内的药动学与生物利用度研究。结果:合成了目标化合物二氢齐墩果酸甲酯(化合物1),其结构经1H NMR,13C NMR和MS确定,总产率为36.6%;药动学试验表明二氢齐墩果酸甲酯在大鼠体内的药-时曲线特征符合血管外给药一级吸收二室模型,大鼠经灌胃(ig)、静脉注射(iv)给药,得到二氢齐墩果酸甲酯的绝对生物利用度为40.96%。结论:相对于齐墩果酸0.7%的绝对生物利用度,双键还原并成酯后生物利用度提高了58倍;同时建立了符合生物样品测定要求的LC/MS/MS分析方法,为相关药动学研究提供参考。Objective： To synthesize methyl dihydrooleanolate and evaluate its pharmacokinetic profiles and absolute bioavailability in rats. Methods： The target compound was synthesized through esterification,acetylation,oxidation,Huang-Minlon reduction,and final esterification. The concentration of target compound in rats plasma was determined by using UPLC-QTOF mass spectrometer. Results： Methyl dihydrooleanolate（1） obtained via 5 steps reaction with an overall yield of 36. 6%,which was verified by^1 H-NMR,^13 C-NMR and ESI-MS. The drug concentration-time curve of 1 from pharmacokinetic experiment indicated that it fitted a two-compartment model with first order absorption of 1 in rats. The absolute bioavailability of 1 was 40. 96% from intragastric administration and intravenous injection. Conclusion： Compound 1,which was prepared via double bond reduction and carboxyl esterification of oleanlic acid（OA）,showed about 58-fold higher than that of OA（0. 7%）. Meanwhile,an LC/MS/MS analytic method was also established for the detection of biological samples,which may provide a reference for the in vivo analysis of OA and its derivatives.

关 键 词：二氢齐墩果酸甲酯 合成 药动学 生物利用度 

分 类 号：R969.1[医药卫生—药理学]