[利用培养的人类/动物隐窝衍生肠干细胞预测药物的肠道吸收和药物引起的肠道毒性]。

Kazuya Maeda
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引用次数: 0

摘要

预测肠道药物吸收和药物引起的肠道毒性对于口服药物的开发至关重要。然而,由于物种差异大和缺乏合适的体外检测方法,很难准确预测这些事件。因此,我们提出利用人体隐窝衍生肠道细胞来预测肠道吸收和肠道毒性风险。我们使用含有 Wnt3a、R-软骨素 3 和 noggin 的条件培养基,从空肠近端和回肠末端的新鲜手术标本中建立了三维人类肠球体。为了生成二维单层细胞,将球体酶解成单个细胞,并将其移植到预先涂有 Matrigel 的培养板/插入物上。我们证实了典型药物代谢酶和摄取/外流转运体在人空肠球状衍生分化细胞中的活性。根据空肠单层从顶端到基底的渗透清除率估算出的肠道可用率(Fg)显示,五种 CYP3A 底物药物的肠道可用率(Fg)与人体体内的 Fg 值有很好的相关性。在预测肠道毒性方面,我们发现不同的表皮生长因子受体-TKIs培养的肠球体中ATP的下降程度因药物而异,且ATP下降程度的排序与临床观察到的腹泻频率的排序一致。我们还构建了富含肠石蜡(EC)细胞的球形体,并量化了EC细胞在暴露于药物时释放的血清素,以预测药物引起的恶心和呕吐。结果我们发现,血清素的释放与每种ALK/ROS1激酶抑制剂引起恶心和呕吐的风险高低有关。
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[Prediction of the drug intestinal absorption and drug-induced intestinal toxicity with the use of cultured human/animal crypt-derived intestinal stem cells].

Prediction of intestinal drug absorption and drug-induced intestinal toxicity is critical for the development of orally-administered drugs. However, it is difficult to accurately predict these events because of large species differences and a lack of appropriate in vitro assay. Then, we proposed the use of human crypt-derived intestinal cells for the prediction of intestinal absorption and the risk of intestinal toxicity. 3D human intestinal spheroids were established from fresh surgical specimens of proximal jejunum and terminal ileum using the conditioned media containing Wnt3a, R-spondin 3, and noggin. To generate 2D monolayer, spheroids were enzymatically dissociated into single cells and plated onto Matrigel-precoated culture plates/inserts. We have confirmed the activities of typical drug-metabolizing enzymes and uptake/efflux transporters in human jejunal spheroid-derived differentiated cells. Intestinal availability (Fg) estimated from the apical-to-basal permeation clearance across the jejunal monolayer showed a good correlation with in vivo human Fg values for five CYP3A substrate drugs. As for the prediction of intestinal toxicity, we found that the degree of ATP decreases in intestinal spheroids incubated with different EGFR-TKIs varied greatly depending on the drugs and the rank order of the extent of ATP decrease corresponded with that of frequency of clinically-observed diarrhea. We also constructed enterochromaffin (EC) cell-rich spheroids and quantified serotonin release from EC cells upon exposure to drugs for the prediction of drug-induced nausea and vomiting. As a result, we found that the serotonin release was related to the high/low risk of nausea and vomiting of each ALK/ROS1 kinase inhibitors.

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来源期刊
Folia Pharmacologica Japonica
Folia Pharmacologica Japonica Pharmacology, Toxicology and Pharmaceutics-Pharmacology
CiteScore
0.40
自引率
0.00%
发文量
132
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