Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury

doi:10.1124/dmd.115.064121

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	Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury
	Li, Xiuli; Zhong, Kan; Guo, Zitao; Zhong, Dafang; Chen, Xiaoyan
刊名	Drug metabolism and disposition: the biological fate of chemicals
	2015-11
卷号	43 期号:11 页码:1751-9
ISSN号	1521-009X
DOI	10.1124/dmd.115.064121
文献子类	Article
英文摘要	Fasiglifam (TAK-875), a selective G-protein-coupled receptor 40 agonist, was developed for the treatment of type 2 diabetes mellitus; however, its development was terminated in phase III clinical trials because of liver safety concerns. Our preliminary study indicated that intravenous administration of 100 mg/kg of TAK-875 increased the serum total bile acid concentration by 3 to 4 times and total bilirubin levels by 1.5 to 2.6 times in rats. In the present study, we examined the inhibitory effects of TAK-875 on hepatobiliary transporters to explore the mechanisms underlying its hepatotoxicity. TAK-875 decreased the biliary excretion index and the in vitro biliary clearance of d₈-taurocholic acid in sandwich-cultured rat hepatocytes, suggesting that TAK-875 impaired biliary excretion of bile acids, possibly by inhibiting bile salt export pump (Bsep). TAK-875 inhibited the efflux transporter multidrug resistance-associated protein 2 (Mrp2) in rat hepatocytes using 5 (and 6)-carboxy-2',7'-dichlorofluorescein as a substrate. Inhibition of MRP2 was further confirmed by reduced transport of vinblastine in Madin-Darby canine kidney cells overexpressing MRP2 with IC₅₀ values of 2.41 μM. TAK-875 also inhibited the major bile acid uptake transporter Na(+)/taurocholate cotransporting polypeptide (Ntcp), which transports d₈-taurocholic acid into rat hepatocytes, with an IC₅₀ value of 10.9 μM. TAK-875 significantly inhibited atorvastatin uptake in organic anion transporter protein (OATP) 1B1 and OATP1B3 cells with IC₅₀ values of 2.28 and 3.98 μM, respectively. These results indicate that TAK-875 inhibited the efflux transporter MRP2/Mrp2 and uptake transporters Ntcp and OATP/Oatp, which may affect bile acid and bilirubin homeostasis, resulting in hyperbilirubinemia and cholestatic hepatotoxicity.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266335]
专题	上海药物代谢研究中心
通讯作者	Chen, Xiaoyan
作者单位	Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
推荐引用方式 GB/T 7714	Li, Xiuli,Zhong, Kan,Guo, Zitao,et al. Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury[J]. Drug metabolism and disposition: the biological fate of chemicals,2015,43(11):1751-9.
APA	Li, Xiuli,Zhong, Kan,Guo, Zitao,Zhong, Dafang,&Chen, Xiaoyan.(2015).Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury.Drug metabolism and disposition: the biological fate of chemicals,43(11),1751-9.
MLA	Li, Xiuli,et al."Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury".Drug metabolism and disposition: the biological fate of chemicals 43.11(2015):1751-9.