Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4

doi:10.1021/acs.molpharmaceut.6b00129

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	Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4
	Yu, Zongjiang 1; Sun, Weizhi2 ; Peng, Weibing 1; Yu, Rilei 1; Li, Guoqiang 1; Jiang, Tao 1
	2016-05-01
发表期刊	MOLECULAR PHARMACEUTICS
卷号	13 期号:5 页码:1699-1710
摘要	Oleanolic acid (OA) is a well-known pentacyclic triterpenoid compound, which has been used as a dietary supplement and is supplied as an over-the-counter drug for the treatment of human liver diseases. These are reasons for the low bioavailability of OA which have restricted its wider application. In this study, two OA prodrugs (1,3-cyclic propanyl phosphate esters of OA) were designed and synthesized. The hepatoprotective effects of these prodrugs were evaluated against carbon tetrachloride (CCl4) induced liver injury in mice; the levels of alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and aspartate aminotransferase (AST) were significantly increased, and the level of the hepatic malondialdehyde (MDA) was increased. The metabolism, in vitro, of the prodrugs was studied by incubation in rat liver microsome; the plasma pharmacokinetics and the biodistribution in vivo after intravenous (iv) injection to six rats were investigated, respectively. The prodrugs diminished gradually with time; most of the parent drugs were released within 30 min in vitro, and the presumed mechanism of the in vitro metabolism was confirmed. The plasmaconcentration data in vivo was analyzed by a compartmental method: both the prodrugs and the corresponding released parent drugs existed at up to 48 h in rats. The t1/2 improved after intravenous administration in rats compared with direct injection of the parent drugs. All analyte concentrations were highest in the liver, and most of the prodrugs were excreted in feces (>47.11%). Therefore, 1,3-cyclic propanyl phosphate esters of OA can serve as a promising lead candidate for drugs.
文章类型	Article
关键词	Oleanolic Acid (Oa) Prodrug Hepatoprotective Pharmacokinetics Biodistribution
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
DOI	10.1021/acs.molpharmaceut.6b00129
关键词[WOS]	PROPANYL PHOSPHATE ESTER ; MICE ; METABOLISM ; DERIVATIVES ; EXTRACT ; SERUM ; MICROSOMES ; DESIGN ; PLASMA ; FECES
收录类别	SCI
语种	英语
WOS研究方向	Research & Experimental Medicine ; Pharmacology & Pharmacy
项目资助者	Natural Science Foundation of China(81373322) ; Key International Cooperation Project of CMST(2013DFG32160) ; NSFC-Shandong Joint Fund(U1406402)
WOS类目	Medicine, Research & Experimental ; Pharmacology & Pharmacy
WOS记录号	WOS:000375519600026
引用统计
文献类型	期刊论文
条目标识符	http://ir.qibebt.ac.cn/handle/337004/8319
专题	生物基材料组群
作者单位	1.Ocean Univ China, Sch Pharm, Minist Educ China, Key Lab Marine Drugs, Qingdao 266003, Peoples R China 2.Chinese Acad Sci, Qingdao Inst Bioenergy & Bioproc Technol, CAS Key Lab Biobased Mat, Qingdao 266101, Peoples R China
推荐引用方式 GB/T 7714	Yu, Zongjiang,Sun, Weizhi,Peng, Weibing,et al. Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4[J]. MOLECULAR PHARMACEUTICS,2016,13(5):1699-1710.
APA	Yu, Zongjiang,Sun, Weizhi,Peng, Weibing,Yu, Rilei,Li, Guoqiang,&Jiang, Tao.(2016).Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4.MOLECULAR PHARMACEUTICS,13(5),1699-1710.
MLA	Yu, Zongjiang,et al."Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4".MOLECULAR PHARMACEUTICS 13.5(2016):1699-1710.