Vol. 303, Issue 2, 574-580, November 2002

Secretory Transport of Ranitidine and Famotidine across Caco-2 Cell Monolayers

Kiho Lee, Chee Ng, Kim L. R. Brouwer and Dhiren R. Thakker

Division of Drug Delivery and Disposition, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

The secretory transport of the H₂-antagonists, ranitidine and famotidine, across Caco-2 cell monolayers was found to be a saturable process. Both drugs exhibited greater permeability in the basolateral (BL) to apical (AP) direction than in the AP to BL direction, indicating apically directed secretion; BL to AP transport was inhibited by P-glycoprotein (P-gp) inhibitors verapamil and cyclosporin A. The cellular uptake of ranitidine across the BL membrane was saturable and temperature dependent, indicative of carrier-mediated transport. The K_m and V_max for the uptake process were estimated to be 66.9 mM and 20.9 nmol/mg of protein/min, respectively. The uptake of [¹⁴C]ranitidine across the BL membrane was inhibited by unlabeled ranitidine and structurally diverse organic cations. The tetraethylammonium (TEA)-sensitive organic cation transporters are not involved in the uptake of ranitidine and famotidine across the BL membrane of Caco-2. This conclusion was based on the evidence that functionally active TEA-sensitive organic cation transporters did not exist in the BL membranes of the Caco-2 cells, whereas the functionally active TEA-sensitive organic cation transporter(s) in LLC-PK₁ cells did not contribute to the transport of ranitidine or famotidine across the cell monolayers. Thus, we conclude that the secretory transport of ranitidine and famotidine across Caco-2 cell monolayers is mediated by 1) a carrier in the BL membrane that is distinct from the TEA-sensitive organic cation transporter(s) and 2) P-gp in the apical membrane.