Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate

doi:10.1124/dmd.110.037614

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	Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate
	Lu, Youli 1; Bao, Narisu 2; Borjihan, Gereltu 2; Ma, Yanling 1; Hu, Miaomiao 1; Yu, Chen 3; Li, Shuijun 3; Jia, Jingying 3; Yang, Ding 1; Wang, Yiping1
刊名	DRUG METABOLISM AND DISPOSITION
	2011-05
卷号	39 期号:5 页码:796-802
ISSN号	0090-9556
DOI	10.1124/dmd.110.037614
文献子类	Article
英文摘要	Ethyl piperate is an effective lipid-lowering drug candidate synthesized from piperine. However, its pharmacokinetic characteristics and oral absorption process remain unclear. A liquid chromatography-tandem mass spectrometry method was applied to determine the oral bioavailability of ethyl piperate. Simulated gastrointestinal pH conditions and intestinal washings were prepared to investigate their contributions to the loss of ethyl piperate. Hydrolysis by carboxylesterase (CES) was evaluated in vitro using microsomes and S9 fractions. In situ intestinal single-pass perfusion experiments were performed to estimate the role of CES in ethyl piperate absorption. The bioavailability of ethyl piperate was extremely low (0.47%) in hamster independent of gastrointestinal environmental effects. Ethyl piperate was a typical substrate of CES with kinetic parameters K-m and V-max of 7.56 +/- 1.491 mu M and 0.16 +/- 0.008 nmol . min(-1) . mg protein(-1), respectively. CES was responsible for 85.8% of the intestinal hydrolysis of ethyl piperate. Specific inhibition of CES with bis-p-nitrophenyl phosphate (BNPP), decreased degradation clearance to 36% of control with no significant change in absorption clearance. This contrasted with the results of Caco-2 monolayer experiments, which showed a dramatic increase in the apparent permeability coefficient after BNPP treatment. mRNA levels for the CES isozyme, CES2A3, were similar among the three regions of hamster intestine and 60% less than those in liver; CES1B1 mRNA levels were even lower in the intestine and showed a proximal-to-distal decrease. In conclusion, CES markedly contributes to intestinal first-pass hydrolysis of ethyl piperate that is sufficient, but not necessary, to cause the observed extremely low bioavailability.
资助项目	National Basic Research Program of China[2009CB930300] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2009ZX09301-001]
WOS关键词	IN-VITRO ; PIPERINE ; RAT ; CACO-2 ; ATHEROSCLEROSIS ; PERMEABILITY ; INHIBITION ; HYDROLYSIS ; METABOLISM ; ABSORPTION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000289619600010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278550]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Wang, Yiping
作者单位	1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Inner Mongolia Univ, Inst Macromol Chem & Mongolian Med, Hohhot, Inner Mongolia, Peoples R China; 3.Shanghai Xuhui Cent Hosp, Cent Lab, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Lu, Youli,Bao, Narisu,Borjihan, Gereltu,et al. Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate[J]. DRUG METABOLISM AND DISPOSITION,2011,39(5):796-802.
APA	Lu, Youli.,Bao, Narisu.,Borjihan, Gereltu.,Ma, Yanling.,Hu, Miaomiao.,...&Wang, Yiping.(2011).Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate.DRUG METABOLISM AND DISPOSITION,39(5),796-802.
MLA	Lu, Youli,et al."Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate".DRUG METABOLISM AND DISPOSITION 39.5(2011):796-802.