Mathia Neil R, Timoszyk Julita, Stetsko Paul I, Megill John R, Smith Ronald L, Wall Doris A
Department of Exploratory Biopharmaceutics and Drug Delivery, Bristol-Myers, New Brunswick, NJ 08903-0191, USA.
J Drug Target. 2002 Feb;10(1):31-40. doi: 10.1080/10611860290007504.
The goal of this study was to evaluate the permeability characteristics of Calu-3, human bronchial epithelial cells to passive and actively transported drugs and to correlate the data with other in vitro models and rat lung absorption in vivo. Air-interface cultured Calu-3 cells grown on collagen-coated permeable filter supports formed "tight" polarized and well differentiated cell monolayers with apical microvilli and tight-junctional complexes. Within 8-10 days, cell monolayers developed trans-epithelial electrical resistance (TEER) > 1000 ohm cm2 and potential difference about 11-16 mV. Solute permeability was dependent on lipophilicity, and inversely related to molecular size. Calu-3 cells actively transported amino acids, nucleosides and dipeptide analogs, but not organic anions, organic cations or efflux pump substrates. The permeability characteristics of Calu-3 cells correlated well with primary cultured rabbit tracheal epithelial cells in vitro (r2 = 0.91), and the rate of drug absorption from the rat lung in vivo (r2 = 0.94). The absorption predicted from the regression equation correlated well with observed values. In conclusion, in vitro-in vivo correlation studies indicate that the Calu-3 cell culture model is a potentially useful model to predict absorption of inhalation delivery drug candidates.
本研究的目的是评估人支气管上皮细胞Calu-3对被动转运和主动转运药物的通透性特征，并将这些数据与其他体外模型以及大鼠体内肺吸收情况进行关联。在胶原包被的可渗透滤膜支架上生长的气液界面培养的Calu-3细胞形成了具有顶端微绒毛和紧密连接复合物的“紧密”极化且分化良好的细胞单层。在8至10天内，细胞单层的跨上皮电阻（TEER）>1000欧姆·平方厘米，电位差约为11至16毫伏。溶质通透性取决于亲脂性，且与分子大小呈负相关。Calu-3细胞可主动转运氨基酸、核苷和二肽类似物，但不能转运有机阴离子、有机阳离子或外排泵底物。Calu-3细胞的通透性特征与体外原代培养的兔气管上皮细胞相关性良好（r2 = 0.91），与大鼠体内肺的药物吸收速率相关性良好（r2 = 0.94）。由回归方程预测的吸收情况与观测值相关性良好。总之，体外-体内相关性研究表明，Calu-3细胞培养模型是预测吸入给药候选药物吸收的潜在有用模型。
