Possible Regulation of P-glycoprotein Function by Adrenergic Agonists in a Vascular-luminal Perfused Preparation of Small Intestine

Hironori Mukai, Masashi Takanashi, Ken-ichi Ogawara, Masato Maruyama, Kazutaka Higaki

Research output: Contribution to journalArticlepeer-review

Abstract

Although the functions of small intestine are largely regulated by enteric nervous system (ENS), an independent intrinsic innervation, as well as central nervous system (CNS), the neural regulation of drug absorption from the small intestine still remains to be clarified. To obtain some information on it, the effect of adrenergic agonists on P-glycoprotein (P-gp) function was investigated by utilizing a vascular-luminal perfused rat small intestine. Adrenaline significantly decreased the secretion of rhodamine-123 (R-123) into the intestinal lumen, but dibutyryl cAMP (DBcAMP) significantly enhanced R-123 secretion. The inhibition study with quinidine clearly indicated that the decrease in secretory clearance of R-123 by adrenaline or the increase by DBcAMP would be attributed to the decrease or increase in P-gp activity, respectively. Expression levels of P-gp in whole mucosal homogenates were not changed at all by any chemicals examined, but those on brush border membrane (BBM) of intestinal epithelial cells were significantly decreased or increased by adrenaline or DBcAMP, respectively. Furthermore, changes in P-gp activity caused by adrenergic agonists and DBcAMP were significantly correlated with changes in expression level of P-gp in BBM, suggesting that the trafficking of P-gp from cytosolic pool to BBM would be regulated by adrenergic agonists and DBcAMP.

Original languageEnglish
JournalJournal of Pharmaceutical Sciences
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • Adrenergic agonist
  • Brush border membrane
  • cAMP
  • Enteric nervous system
  • Intestinal absorption
  • Intestinal secretion
  • P-glycoprotein
  • Rhodamine-123
  • Trafficking
  • Western blot

ASJC Scopus subject areas

  • Pharmaceutical Science

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