title: Effect of adrenergic stimulation on drug absorption via passive diffusion in Caco-2 cells.
abstract: It is well known that the enteric nervous system (ENS) regulates the movement and function of the small intestine, but the effects of ENS on drug absorption from the small intestine still remain to be clarified. Focusing on adrenergic effect, we tried to evaluate how adrenergic stimulation influences the drug absorption via passive diffusion using Caco-2 cells as model epithelial cells, a terminal effector of ENS. Adrenaline, an adrenergic agonist, did not affect the transport of small molecules such as antipyrine, phenacetin and mannitol, but decreased the transport of large molecules such as FITC-dextran (FD)-20 and FD-40 without transepithelial electrical resistance (TEER) change. These results suggested that the transport of large molecules via paracellular route would be attenuated by adrenergic stimulation. Only clonidine, an alpha(2)-agonist, among selective adrenoceptor agonists decreased FD-40 transport across Caco-2 cell monolayers and the agonist also decreased intracellular cAMP. Furthermore, H-89, a protein kinase A inhibitor, significantly decreased FD-40 transport and dibutyryl cAMP, a cAMP derivative, increased it. These results suggest that the decrease in FD-40 transport would be mainly attributed to the decrease in intracellular cAMP and subsequent decrease in PKA activity via alpha(2)-receptor stimulation.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kimoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Takanashi
authors.forename: Hironori
authors.initials: H
authors.lastname: Mukai
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Ogawara
authors.forename: Toshikiro
authors.initials: T
authors.lastname: Kimura
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology*; D004058:Diffusion / Q000187:drug effects*; D017615:Enteric Nervous System / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology*; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D003000:Clonidine; D004837:Epinephrine