Transport Mechanism of Intestinal Absorption of ü Opioid Recept or Agonists and Contribution of P-Glycoprotein in Rats and Human Intestinal Epithelial Caco-2

Abstract 1.1. Introduction: The μ opioid receptor agonists, morphine and loperamide, are widely used orally and are suggested to be P-glycoprotein (P-gp) substrates. P-gp is expressed in the brain, intestine, and various tissues in human and rats. In the intestine, P-gp limits the absorption of certain drugs such as opioids; however, the underlying mechanism has not been elucidated. The aim of the present study was to examine the intestinal transport characteristics of morphine and loperamide and the role of P-gp in their transport process. 1.2. Method: Transcellular transport studies were conducted using isolated rat intestinal tissue mounted in an Ussing-type chamber. Bidirectional permeability and inhibition transport studies were performed using Caco-2 cell lines. The intestinal absorption was examined by an in situ closed-loop method in rats. 1.3. Results: Loperamide showed secretory transport across rat intestinal tissue and Caco-2 cells, and P-gp substrates cyclosporine A and rhodamine 123 inhibited this transport. In the intestinal loop experiment in rats, the accumulation of loperamide in the intestinal tissue increased upon adding cyclosporine A and rhodamine 123. In contrast, morphine showed no directional transport and P-gp inhibitory effects across rat intestinal tissue. In Caco-2 cells, morphine transport was found to be secretory-directed and this transport was inhibited by cyclosporine A and rhodamine 123, but to a much lesser extent than that of loperamide. Morphine disappearance and accumulation were unaffected upon the addition of cyclosporine A and rhodamine 123. 1.4. Conclusion: These results suggest that P-gp contributes significantly to the secretory transport of loperamide but negligibly to that of morphine in the small intestine. In conclusion, intestinal transport of both morphine and loperamide is found to be secretory-directed. P-gp partially contributes to this secretory-directed transport. Thus, P-gp is prominent in loperamide rather than morphine transport.