Novel cation-sensitive mechanisms for intestinal absorption and secretion of famotidine and ranitidine: Potential clinical implications

The small intestine is the major route of entry for orally administered drugs. Many organic cations are incompletely absorbed after oral administration and also may be secreted actively in the intestine. However, detailed mechanisms responsible for the oral absorption and secretion of organic cations are not fully understood. Famotidine and ranitidine were selected as model hydrophilic organic cationic compounds for this project. The H₂-receptor antagonist, ranitidine, is secreted into the intestine in human and rat. Recent in vitro studies using Caco-2 cell monolayers suggest that the secretory transport of ranitidine occurs via the transcellular pathway and involves a basolateral (BL) uptake mechanism mediated by an unknown transporter. The first objective of this dissertation project was to (1) determine whether recently cloned organic cation transport proteins (OCTs and OCTNs) are present in Caco-2 cells, and (2) study the role of these transporters in ranitidine transport across the BL membrane of Caco-2 cells. The present studies indicated that OCT and OCTN transporter families are not responsible for the BL uptake of ranitidine in Caco-2 cells because (1) OCT and OCTN are not functionally active in the BL membrane of Caco-2 cells as a substrate specific for these transporters, TEA, was not transported across the BL membrane of Caco-2 cells; (2) TEA did not inhibit the BL uptake of ranitidine in Caco-2 cells; and (3) driving forces for BL uptake of ranitidine in Caco-2 cells are distinct from any of the cloned organic cation transporters. The second objective of this dissertation project was to determine whether a clinically significant interaction between two organic cations sharing a common transport process for absorption can be demonstrated in healthy human volunteers. Four healthy, nonobese, medication-free subjects (1 male, 3 females; mean age, 20.3 yr) were enrolled. Oral ranitidine significantly reduced oral famotidine bioavailability from 0.42 ± 0.07 to 0.25 ± 0.07 (p < 0.05). Ranitidine significantly decreased the total amount of famotidine absorbed and zero-order absorption rate constant in the zero-order absorption phase. The time to complete absorption of oral famotidine was significantly shorter in the presence of oral ranitidine. These results demonstrate that a clinically significant interaction exists in the oral absorption of famotidine in the presence of ranitidine. A ranitidine-sensitive saturable transport process may play an important role in the oral absorption of famotidine in humans. (Abstract shortened by UMI.)...