Possible Regulation of P-Glycoprotein Function by Adrenergic Agonists II: Study with Isolated Rat Jejunal Sheets and Caco-2 Cell monolayers.

To clarify the regulation of drug absorption by the enteric nervous system, we investigated how adrenergic agonists (adrenaline (ADR), clonidine (CLO), dobutamine (DOB)) and dibutyryl cAMP (DBcAMP) affected P-glycoprotein (P-gp) function by utilizing isolated rat jejunal sheets and Caco-2 cell monolayers. ADR and CLO significantly decreased the secretory transport (P _app ^total ) of rhodamine-123 and tended to decrease the transport via P-gp (P _app ^P-gp ) and passive transport (P _app ^passive ). In contrast, DBcAMP significantly increased and DOB tended to increase P _app ^total and both tended to increase P _app ^P-gp and P _app ^passive . Changes in P-gp expression on brush border membrane by adrenergic agonists and DBcAMP were significantly correlated with P _app ^P-gp , while P-gp expression was not changed in whole cell homogenates, suggesting that the trafficking of P-gp would be responsible for its functional changes. P _app ^passive was inversely correlated with transmucosal or transepithelial electrical resistance, indicating that adrenergic agonists affected the paracellular permeability. Adrenergic agonists also changed cAMP levels, which were significantly correlated with P _app ^P-gp . Furthermore, protein kinase A (PKA) or PKC inhibitor significantly decreased P _app ^P-gp in Caco-2 cell monolayers, suggesting that they would partly contribute to the changes in P-gp activity. In conclusion, adrenergic agonists regulated P-gp function and paracellular permeability, which would be caused via adrenoceptor stimulation.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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