Gan L S, Hsyu P H, Pritchard J F, Thakker D
Department of Drug Metabolism, Glaxo Inc., Research Triangle Park, North Carolina 27709.
Pharm Res. 1993 Dec;10(12):1722-5. doi: 10.1023/a:1018965929419.
We have investigated the transport of ranitidine and ondansetron across the Caco-2 cell monolayers. The apparent permeability co-efficients (Papp) were unchanged throughout the concentration range studied, indicating a passive diffusion pathway across intestinal mucosa. No metabolism was observed for ranitidine and ondansetron during the incubation with Caco-2 cell monolayers. Papp values for ranitidine and ondansetron (bioavailability of 50 and approximately 100% in humans, respectively) were 1.03 +/- 0.17 x 10(-7) and 1.83 +/- 0.055 x 10(-5) cm/sec, respectively. The Papp value for ranitidine was increased by 15- to 20-fold in a calcium-free medium or in the transport medium containing EDTA, whereas no significant change occurred with ondansetron, indicating that paracellular passive diffusion is not rate determining for ondansetron. Uptake of ondansetron by Caco-2 cell monolayers was 20- and 5-fold higher than that of ranitidine when the uptake study was carried out under sink conditions and at steady state. These results suggest that ranitidine and ondansetron are transported across Caco-2 cell monolayers predominantly via paracellular and transcellular pathways, respectively.
我们研究了雷尼替丁和昂丹司琼透过Caco-2细胞单层的转运情况。在所研究的浓度范围内，表观渗透系数（Papp）没有变化，这表明其通过肠道黏膜的途径为被动扩散。在与Caco-2细胞单层共同孵育期间，未观察到雷尼替丁和昂丹司琼发生代谢。雷尼替丁和昂丹司琼的Papp值（在人体中的生物利用度分别为50%和约100%）分别为1.03±0.17×10⁻⁷和1.83±0.055×10⁻⁵cm/秒。在无钙培养基或含有乙二胺四乙酸（EDTA）的转运培养基中，雷尼替丁的Papp值增加了15至20倍，而昂丹司琼没有显著变化，这表明细胞旁被动扩散不是昂丹司琼的限速因素。当在漏槽条件和稳态下进行摄取研究时，Caco-2细胞单层对昂丹司琼的摄取比雷尼替丁高20倍和5倍。这些结果表明，雷尼替丁和昂丹司琼分别主要通过细胞旁和跨细胞途径透过Caco-2细胞单层。
