INVESTIGATION OF RAPAMYCIN TRANSPORT AND UPTAKE ACROSS ABSORPTIVE HUMAN INTESTINAL-CELL MONOLAYERS
INVESTIGATION OF RAPAMYCIN TRANSPORT AND UPTAKE ACROSS ABSORPTIVE HUMAN INTESTINAL-CELL MONOLAYERS
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DOI：
10.1016/0009-9120(94)90008-6
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发表时间：
1994-02-01
影响因子：
2.8
通讯作者：
YATSCOFF, RW
中科院分区：
文献类型：
--
作者：
DIAS, VC;YATSCOFF, RW
体外肠细胞培养模型用于表征和研究影响雷帕霉素（RAPA），一种有效的免疫抑制药物的摄取和转运的因素。对在微孔膜插入物上生长12天的三种人肠细胞单层（Caco-2、HCT-8和T84）进行研究。RAPA运输在所有三个单层被认为是剂量依赖性的。最高的转运率发现在最高测试的最终RAPA浓度10，000 μ g/L。顶部至基底RAPA运输在Caco-2细胞单层中为线性长达60分钟，在HCT-8和T84细胞单层中为线性长达120分钟。发现温度敏感的RAPA运输，因为在4 ℃下孵育显著衰减运输97，90和78%，分别为Caco-2，HCT-8和T84单层。在所有三个单层RAPA运输是高度极化的，因为顶端到基底的运输大于在相反的方向。当10，000 μ g/L RAPA（冷）加0.05 μ Ci C-14-RAPA与不同终浓度（1，000、10，000和100，000 μ g/L）的免疫抑制药物CsA或RS组合加入时，比较RAPA的摄取和跨细胞单层的转运。CsA浓度的增加导致C-14-RAPA跨细胞单层转运的显著剂量依赖性降低。相反，在高浓度（100，000微克/升）RS，C-14-RAPA运输显着增加。仅当CsA浓度为100，000 μ g/L时，细胞单层对C-14-RAPA的摄取才显著降低。这些研究表明，口服免疫抑制药物的组合有可能改变RAPA的肠道转运和摄取。目前正在使用这种细胞模型进行更多的研究，使用其他免疫抑制药物的多种组合，以及在动物体内进一步研究这一点。
An in vitro intestinal cell culture model was used to characterize and investigate factors affecting uptake and transport of rapamycin (RAPA), a potent immunosuppressive drug. Studies were performed on three human intestinal cell monolayers (Caco-2, HCT-8, and T84), grown on microporous membrane inserts for 12 days. RAPA transport in all three monolayers was found to be dose dependent. The highest rates of transport were found at the highest tested final RAPA concentration of 10,000 mu g/L. Apical to basal RAPA transport was linear in Caco-2 cell monolayers for up to 60 min, and in HCT-8 and T84 cell monolayers for up to 120 min. Temperature sensitive RAPA transport was found because incubation at 4 degrees C markedly attenuated transport by 97, 90, and 78% for Caco-2, HCT-8, and T84 monolayers, respectively. In all three monolayers RAPA transport was highly polarized because the apical to basal transport was greater than that in the opposite direction. RAPA uptake and transport across cell monolayers were compared when 10,000 mu g/L of RAPA (cold) plus 0.05 mu Ci C-14-RAPA was added in combination with varying final concentrations (1,000, 10,000, and 100,000 mu g/L) of the immunosuppressive drugs, CsA or RS. Increasing concentrations of CsA resulted in a significant dose-dependent decrease in C-14-RAPA transport across cell monolayers. In contrast, at high (100,000 mu g/L) RS concentrations, C-14-RAPA transport was significantly increased. Uptake of C-14-RAPA into cell monolayers was significantly decreased only with the 100,000 mu g/L CsA concentration. These studies suggest that combinations of immunosuppressive drugs given orally have a potential for altering the intestinal transport and uptake of RAPA. More studies are currently being performed with this cell model using multiple combinations of other immunosuppressive drugs, as well as in vivo in animals to further investigate this.