Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans

doi:10.1124/dmd.118.085092

	Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans
	Li, Xiuli 1; Sun, Jingchao 2; Guo, Zitao 1; Zhong, Dafang 1; Chen, Xiaoyan 1
刊名	DRUG METABOLISM AND DISPOSITION
	2019-08-01
卷号	47 期号:8 页码:843-853
ISSN号	0090-9556
DOI	10.1124/dmd.118.085092
通讯作者	Chen, Xiaoyan(xychen@simm.ac.cn)
英文摘要	Exp3174 is an active metabolite of losartan for the treatment of hypertension. Allisartan (ALS3) is a marketed ester prodrug of Exp3174 to reduce bioavailability variation of losartan in China. However, ALS3 exhibited a lower oral absorption than losartan in humans. In this study, the enzymes and transporters involved in ALS3 and Exp3174 disposition were investigated to clarify the mechanisms. ALS3 underwent extensive hydrolysis to Exp3174 in S9 of Caco-2 cells, human intestine microsomes (HIM), recombinant carboxyles-terase (rCES) 1, and rCES2. ALS3 exhibited similar affinity in HIM and rCES2 with K-m values of 6.92 and 6.77 mu M, respectively, indicating that ALS3 is mainly hydrolyzed to Exp3174 in human intestine by CES2. Transport assays of ALS3 and Exp3174 suggested that ALS3 and Exp3174 are substrates of P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 2 with poor permeability. Organic anion-transporting polypeptide 2B1 showed higher affinity and clearance toward ALS3 (K-m 0.75 mu M and intrinsic clearance 215 mu l/min/mg) than those of Exp3174 (K-m 7.85 mu M and intrinsic clearance 16.1 mu l/min/mg), indicating that ALS3 is preferred to be uptaken into intestinal epithelia. Hydrolysis of ALS3 was increased from approximately 30% to 55% in CES2-transfected human embryonic kidney 293-OATP2B1 cells, indicating the possible interplay between OATP2B1 and CES2. The influx and efflux of ALS3 across Caco-2 cells increased the potential of ALS3 hydrolysis to Exp3174, and the produced Exp3174 was rapidly pumped out, which led to undetectable ALS3 and Exp3174 in basolateral (receiver) side in Caco-2 cells. Overall, our study provided supportive evidences that the interplay between CES2 and transporters in intestine contributes to the low bioavailability of ALS3 in humans.
资助项目	Young Science Foundation of the National Natural Science Foundation of China[81703602] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050306]
WOS关键词	HUMAN ARYLACETAMIDE DEACETYLASE ; II RECEPTOR ANTAGONIST ; HUMAN LIVER-MICROSOMES ; CACO-2 CELLS ; EFFLUX TRANSPORTERS ; IN-VITRO ; LOSARTAN ; METABOLITE ; ABSORPTION ; ENZYME
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000480438000001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288943]
专题	中国科学院上海药物研究所
通讯作者	Chen, Xiaoyan
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 2.Shenzhen Salubris Pharmaceut, Shenzhen, Guangdong, Peoples R China
推荐引用方式 GB/T 7714	Li, Xiuli,Sun, Jingchao,Guo, Zitao,et al. Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans[J]. DRUG METABOLISM AND DISPOSITION,2019,47(8):843-853.
APA	Li, Xiuli,Sun, Jingchao,Guo, Zitao,Zhong, Dafang,&Chen, Xiaoyan.(2019).Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans.DRUG METABOLISM AND DISPOSITION,47(8),843-853.
MLA	Li, Xiuli,et al."Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans".DRUG METABOLISM AND DISPOSITION 47.8(2019):843-853.