Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands.
ALTEX. 2024 Jan 9;41(1):20-36. doi: 10.14573/altex.2302011. Epub 2023 Jul 27.
Bile acid homeostasis is vital for numerous metabolic and immune functions in humans. The enterohepatic circulation of bile acids is extremely efficient, with ~95% of intestinal bile acids being reabsorbed. Disturbing intestinal bile acid uptake is expected to substantially affect intestinal and systemic bile acid levels. Here, we aimed to predict the effects of apical sodium-dependent bile acid transporter (ASBT)-inhibition on systemic plasma levels. For this, we combined in vitro Caco-2 cell transport assays with physiologically based (PBK) modeling. We used the selective ASBT-inhibitor odevixibat (ODE) as a model compound. Caco-2 cells grown on culture inserts were used to obtain transport kinetic parameters of glycocholic acid (GCA). The apparent Michaelis-Menten constant (Km,app), apparent maximal intestinal transport rate (Vmax,app), and ODE’s inhibitory constant (Ki) were determined for GCA. These kinetic parameters were incorporated into a PBK model and used to predict the ASBT inhibition effects on plasma bile acid levels. GCA is transported over Caco-2 cells in an active and sodium-dependent manner, indicating the presence of functional ASBT. ODE inhibited GCA transport dose-dependently. The PBK model predicted that oral doses of ODE reduced conjugated bile acid levels in plasma. Our simulations match in vivo data and provide a first proof-of-principle for the incorporation of active intestinal bile acid uptake in a bile acid PBK model. This approach could in future be of use to predict the effects of other ASBT-inhibitors on plasma and intestinal bile acid levels.
胆汁酸稳态对于人类的许多代谢和免疫功能至关重要。胆汁酸的肠肝循环效率极高，约 95%的肠道胆汁酸被重吸收。干扰肠道胆汁酸摄取预计会对肠道和全身胆汁酸水平产生重大影响。在这里，我们旨在预测顶端钠依赖性胆汁酸转运体（ASBT）抑制对系统血浆水平的影响。为此，我们将体外 Caco-2 细胞转运测定与基于生理学的（PBK）模型相结合。我们使用选择性 ASBT 抑制剂奥贝胆酸（ODE）作为模型化合物。在培养插入物上生长的 Caco-2 细胞用于获得甘氨胆酸（GCA）的转运动力学参数。确定了 GCA 的表观米氏常数（Km，app）、表观最大肠内转运速率（Vmax，app）和 ODE 的抑制常数（Ki）。这些动力学参数被纳入 PBK 模型，并用于预测 ASBT 抑制对血浆胆汁酸水平的影响。GCA 以主动和钠离子依赖性方式在 Caco-2 细胞中转运，表明存在功能性 ASBT。ODE 剂量依赖性地抑制 GCA 转运。PBK 模型预测口服 ODE 剂量会降低血浆中结合型胆汁酸水平。我们的模拟与体内数据相匹配，并为在胆汁酸 PBK 模型中纳入主动肠内胆汁酸摄取提供了第一个原理验证。该方法将来可用于预测其他 ASBT 抑制剂对血浆和肠道胆汁酸水平的影响。
