Intestinal absorptive transport of the hydrophilic cation ranitidine:: A kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs. transcellular transport in caco-2 cells

Purpose: The mechanism of intestinal drug transport for hydrophilic cations such as ranitidine is complex, and evidence suggests a role for carrier-mediated apical (AP) uptake and saturable paracellular mechanisms in their overall absorptive transport. The purpose of this study was to develop a model capable of describing the kinetics of cellular accumulation and transport of ranitidine in Caco-2 cells, and to assess the relative contribution of the transcellular and paracellular routes toward overall ranitidine transport. Methods: Cellular accumulation and absorptive transport of ranitidine were determined in the absence or presence of uptake and efflux inhibitors and as a function of concentration over 60 min in Caco-2 cells. A three-compartment model was developed, and parameter estimates were utilized to assess the expected relative contribution from transcellular and paracellular transport. Results: Under all conditions, ranitidine absorptive transport consisted of significant transcellular and paracellular components. Inhibition of P-glycoprotein decreased the AP efflux rate constant (k(21)) and increased the relative contribution of the transcellular transport pathway. In the presence of quinidine, both the AP uptake rate constant (k(12)) and k(21) decreased, resulting in a predominantly paracellular contribution to ranitidine transport. Increasing the ranitidine donor concentration decreased k(12) and the paracellular rate constant (k(13)). No significant changes were observed in the relative contribution of the paracellular and transcellular routes as a function of ranitidine concentration. Conclusions: These results suggest the importance of uptake and efflux transporters as determinants of the relative contribution of transcellular and paracellular transport for ranitidine, and provide evidence supporting a concentration-dependent paracellular transport mechanism. The modeling approach developed here may also be useful in estimating the relative contribution of paracellular and transcellular transport for a wide array of drugs expected to utilize both pathways.