A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans

被引：30

作者：

Caballero-Camino, Francisco J. ^{[1
,2
]}

Rodrigues, Pedro M. ^{[1
,3
,4
]}

Wangsell, Fredrik ^{[5
]}

Agirre-Lizaso, Alona ^{[1
]}

Olaizola, Paula ^{[1
,3
]}

Izquierdo-Sanchez, Laura ^{[1
,3
]}

Perugorria, Maria J. ^{[1
,2
,3
]}

Bujanda, Luis ^{[1
,2
,3
]}

Angelin, Bo ^{[6
,7
]}

Straniero, Sara ^{[6
,7
]}

Walleback, Anna ^{[5
]}

Starke, Ingemar ^{[5
]}

Gillberg, Per-Goran ^{[5
]}

Strangberg, Ellen ^{[5
]}

Bonn, Britta ^{[5
]}

Mattsson, Jan P. ^{[5
]}

Madsen, Martin R. ^{[8
]}

Hansen, Henrik H. ^{[8
]}

Lindstrom, Erik ^{[5
,11
]}

Akerblad, Peter ^{[5
,11
]}

Banales, Jesus M. ^{[1
,3
,4
,9
,10
]}

机构：

[1] Univ Basque Country UPV EHU, Donostia Univ Hosp, Biodonostia Hlth Res Inst, Dept Liver & Gastrointestinal Dis, San Sebastian, Spain

[2] Univ Basque Country UPV EHU, Fac Med & Nursing, Dept Med, Leioa, Spain

[3] Inst Salud Carlos III, Natl Inst Study Liver & Gastrointestinal Dis, CIBERehd, Madrid, Spain

[4] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

[5] Albireo AB, Gothenburg, Sweden

[6] Karolinska Univ, Hosp Huddinge, Karolinska Inst, Cardiometab Unit,Dept Med, Stockholm, Sweden

[7] Karolinska Univ, Hosp Huddinge, Karolinska Inst, Clin Dept Endocrinol, Stockholm, Sweden

[8] Gubra, Horsholm, Denmark

[9] Univ Navarra, Sch Sci, Dept Biochem & Genet, Pamplona, Spain

[10] Donostia Univ Hosp, Biodonostia Hlth Res Inst, Dept Liver & Gastrointestinal Dis, Paseo Dr Begiristain S-N, E-20014 San Sebastian, Spain

[11] Albireo AB, Arvid Wallgrens Backe 20, S-41346 Gothenburg, Sweden

来源：

HEPATOLOGY | 2023年 / 78卷 / 03期

关键词：

PRIMARY SCLEROSING CHOLANGITIS; BILE-ACID; LIVER; SERUM; TRANSPORTERS; DISRUPTION; CIRRHOSIS; PRURITUS; INJURY; CELLS;

D O I：

10.1097/HEP.0000000000000376

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

Background and Aims: Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans. Approach and Results: A3907 was a potent and selective ASBT inhibitor in vitro. In rodents, orally administered A3907 distributed to the ASBTexpressing organs, that is, ileum, liver, and kidneys, and dose dependently increased fecal BA excretion. A3907 improved biochemical, histological, and molecular markers of liver and bile duct injury in Mdr2(-/-) mice and also had direct protective effects on rat cholangiocytes exposed to cytotoxic BA concentrations in vitro. In bile duct ligated mice, A3907 increased urinary BA elimination, reduced serum BA levels, and prevented body weight loss, while improving markers of liver injury. A3907 was well tolerated and demonstrated target engagement in healthy volunteers. Plasma exposure of A3907 in humans was within the range of systemic concentrations that achieved therapeutic efficacy in mouse. Conclusions: The systemic ASBT inhibitor A3907 improved experimental cholestatic disease by targeting ASBT function at the intestinal, liver, and kidney levels, resulting in marked clearance of circulating BAs and liver protection. A3907 is well tolerated in humans, supporting further clinical development for the treatment of cholestatic liver diseases.

引用

页码：709 / 726

页数：18

共 43 条

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Ileal Bile Acid Transporter Inhibition for the Treatment of Chronic Constipation, Cholestatic Pruritus, and NASH [J].