Collett A, Sims E, Walker D, He Y L, Ayrton J, Rowland M, Warhurst G
Department of Medicine, University of Manchester, Hope Hospital, United Kingdom.
Pharm Res. 1996 Feb;13(2):216-21. doi: 10.1023/a:1016082829111.
To compare the permeability characteristics of HT29-18-C1 colonic epithelial cell line with Caco-2, an established model of intestinal drug transport.
Cell lines were grown as epithelial monolayers. Permeability was measured over a range of transepithelial electrical resistance (Rt) using a group of drug compounds.
HT29-18-C1 develop Rt slowly when grown in culture, allowing permeability to be measured over a wide range (80-600 Omega x cm2). In contrast, Caco-2 monolayers rapidly develop Rt of approximately equal 300 Omega x cm2 and require Ca2+ -chelation to generate Rt equivalent to human intestine (60-120 Omega x cm2). Permeability of atenolol, ranitidine, cimetidine, hydrochlorothiazide and mannitol across HT29-18-C1 decreased 4-5 fold as Rt developed from 100-300 Omega x cm2 indicating they permeate via the paracellular route. In contrast, ondansetron showed no difference in permeability with changing Rt consistent with transcellular permeation. Permeability profiles across low Rt HT29-18C1 and pulse EGTA-treated Caco-2 monolayers were the same for all 5 paracellular drugs suggesting that transient Ca2+ removal does not alter selectivity of the tight junctions. Permeabilities of cimetidine, hydrochlorothiazide and atenolol across 100 Omega x cm2 HT29-18-C1 monolayers reflect more closely those reported for the human ileum in vivo than did mature Caco-2 monolayers.
HT29-18-C1 monolayers can be used to study drug permeability at Rt values similar to human intestine without the need for Ca2+ chelation. As such, they offer a useful alternative to Caco-2 for modelling intestinal drug absorption.
比较HT29 - 18 - C1结肠上皮细胞系与已确立的肠道药物转运模型Caco - 2的通透性特征。
细胞系生长为上皮单层。使用一组药物化合物在一系列跨上皮电阻（Rt）范围内测量通透性。
HT29 - 18 - C1在培养中生长时Rt增长缓慢，使得通透性能够在较宽范围（80 - 600Ω×cm²）内测量。相比之下，Caco - 2单层迅速形成约300Ω×cm²的Rt，并且需要螯合Ca²⁺才能产生与人肠道相当的Rt（60 - 120Ω×cm²）。随着Rt从100 - 300Ω×cm²发展，阿替洛尔、雷尼替丁、西咪替丁、氢氯噻嗪和甘露醇在HT29 - 18 - C1上的通透性降低4 - 5倍，表明它们通过细胞旁途径渗透。相比之下，昂丹司琼的通透性随Rt变化无差异，这与跨细胞渗透一致。对于所有5种细胞旁药物，低Rt的HT29 - 18C1和脉冲EGTA处理的Caco - 2单层的通透性谱相同，表明瞬时去除Ca²⁺不会改变紧密连接的选择性。西咪替丁、氢氯噻嗪和阿替洛尔在100Ω×cm²的HT29 - 18 - C1单层上的通透性比成熟的Caco - 2单层更接近体内人回肠的报道值。
HT29 - 18 - C1单层可用于在与人肠道相似的Rt值下研究药物通透性，而无需Ca²⁺螯合。因此，它们为模拟肠道药物吸收提供了一种有用的替代Caco - 2的方法。
