Hu M, Borchardt R T
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66045.
Pharm Res. 1990 Dec;7(12):1313-9. doi: 10.1023/a:1015906409585.
The Caco-2 model system (Hidalgo et al., Gastroenterology, 96:736-749, 1989), which is a monolayer of polarized intestinal epithelial cells grown onto a porous polycarbonate membrane, was used to study the mechanism of transcellular transport of an antihypertensive agent, L-alpha-methyldopa (L-alpha-MD). The results showed that the transport of L-alpha-MD was pH, glucose, concentration, and temperature dependent, and it could be inhibited by metabolic inhibitors (e.g., 2,4-dinitrophenol) and by amino acids (e.g., L-phenylalanine) which have an affinity for the large neutral amino acid (LNAA) carrier. In addition, the apparent kinetic constants describing the transcellular transport of L-alpha-MD were altered depending on the time interval between feeding the cells and the transport experiments (postfeeding time, PFT). The apparent maximum carrier flux (Jmax) of L-alpha-MD was significantly increased (from 155 to 547 pmol/mg protein/min) when PFT was prolonged from 8.5 to 56 hr. These results indicated that the transcellular transport of L-alpha-MD through the polarized Caco-2 cell monolayer was carrier mediated via the LNAA carrier. The similarities in the characteristics of L-alpha-MD transport exhibited by the Caco-2 model system and other intestinal models in vitro further substantiate the usefulness of this cell culture model for studying the intestinal transport of nutrients and drugs.
Caco-2模型系统（Hidalgo等人，《胃肠病学》，96:736 - 749，1989）是一种生长在多孔聚碳酸酯膜上的极化肠上皮细胞单层，用于研究抗高血压药物L-α-甲基多巴（L-α-MD）的跨细胞转运机制。结果表明，L-α-MD的转运依赖于pH、葡萄糖、浓度和温度，并且可被代谢抑制剂（如2,4-二硝基苯酚）以及对大中性氨基酸（LNAA）载体有亲和力的氨基酸（如L-苯丙氨酸）抑制。此外，描述L-α-MD跨细胞转运的表观动力学常数会根据给细胞喂食与转运实验之间的时间间隔（喂食后时间，PFT）而改变。当PFT从8.5小时延长至56小时时，L-α-MD的表观最大载体通量（Jmax）显著增加（从155增加至547 pmol/mg蛋白质/分钟）。这些结果表明，L-α-MD通过极化的Caco-2细胞单层的跨细胞转运是通过LNAA载体介导的。Caco-2模型系统与其他体外肠道模型所表现出的L-α-MD转运特征的相似性，进一步证实了这种细胞培养模型在研究营养物质和药物肠道转运方面的实用性。
