Zhang Nina, Rietjens Ivonne M C M, de Bruijn Véronique M P
Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
Arch Toxicol. 2025 Mar;99(3):1073-1083. doi: 10.1007/s00204-024-03936-7. Epub 2024 Dec 28.
Systemic bile acid homeostasis plays an important role in human health. In this study, a physiologically based kinetic (PBK) model that includes microbial bile acid deconjugation and intestinal bile acid reuptake via the apical sodium-dependent bile acid transporter (ASBT) was applied to predict the systemic plasma bile acid concentrations in human upon oral treatment with the antibiotic tobramycin. Tobramycin was previously shown to inhibit intestinal deconjugation and reuptake of bile acids and to affect bile acid homeostasis upon oral exposure of rats. Kinetic parameters to define the effects of tobramycin on intestinal bile acid transport were determined in vitro using a Caco-2 cell layer Transwell model for studying the intestinal translocation of 4 model bile acids including glycochenodeoxycholic acid (GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and deoxycholic acid (DCA), the latter as a model for unconjugated bile acids (uBA). Kinetic constants for the effect of tobramycin on intestinal microbial deconjugation were taken from previous in vitro studies using anaerobic fecal incubations. The PBK model simulations predicted that exposure to tobramycin at the dose level also used in the previous 28 day rat study would reduce human plasma C levels of GCA, GCDCA, GDCA, and DCA by 42.4%, 27.7%, 16.9%, and 75.8%. The reduction of conjugated bile acids is governed especially via an effect on ASBT-mediated intestinal uptake, and not via the effect of tobramycin on intestinal conjugation, likely because deconjugation happens to a large extent in the colon which has limited subsequent bile acid reuptake. The results reflect that oral exposure to xenobiotics that are not or poorly bioavailable can affect systemic bile acid homeostasis. Altogether, the PBK model appears to provide a 3R compliant tool to evaluate the effect of oral exposure to xenobiotics on host bile acid homeostasis via effects on intestinal bile acid deconjugation and reuptake.
全身胆汁酸稳态在人类健康中起着重要作用。在本研究中，应用了一种基于生理学的动力学（PBK）模型，该模型包括微生物胆汁酸去结合作用以及通过顶端钠依赖性胆汁酸转运体（ASBT）进行的肠道胆汁酸再摄取，以预测人类口服抗生素妥布霉素后全身血浆胆汁酸浓度。先前的研究表明，妥布霉素可抑制肠道胆汁酸的去结合和再摄取，并在大鼠口服暴露后影响胆汁酸稳态。使用Caco - 2细胞层Transwell模型体外测定了定义妥布霉素对肠道胆汁酸转运影响的动力学参数，该模型用于研究4种模型胆汁酸（包括甘氨鹅脱氧胆酸（GCDCA）、甘胆酸（GCA）、甘氨脱氧胆酸（GDCA）和脱氧胆酸（DCA），后者作为未结合胆汁酸（uBA）的模型）的肠道转运。妥布霉素对肠道微生物去结合作用影响的动力学常数取自先前使用厌氧粪便培养的体外研究。PBK模型模拟预测，以先前28天大鼠研究中也使用的剂量水平暴露于妥布霉素，将使人类血浆中GCA、GCDCA、GDCA和DCA的C水平分别降低42.4%、27.7%、16.9%和75.8%。结合胆汁酸的减少尤其通过对ASBT介导的肠道摄取的影响来控制，而不是通过妥布霉素对肠道结合作用的影响，这可能是因为去结合作用在很大程度上发生在结肠，而结肠随后的胆汁酸再摄取有限。结果表明，口服生物利用度低或无生物利用度的外源化合物可影响全身胆汁酸稳态。总之，PBK模型似乎提供了一种符合3R原则的工具，可通过影响肠道胆汁酸去结合和再摄取来评估口服外源化合物对宿主胆汁酸稳态的影响。
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