The contribution of intestinal secretion to the dose-dependent absorption of celiprolol.
The contribution of the intestine to the nonlinear absorption of celiprolol in the rat was studied. After intravenous administration of 14C-celiprolol to bile duct-cannulated rats, approximately 9% of the dose was found to be associated with intestinal tissue and its contents. Microhistoautoradiography of frozen intestinal sections showed a time-dependent secretion of celiprolol from the blood into the lumen of the rat intestine. Propranolol, a lipophilic beta-blocker, was also found to be secreted into the intestine in vivo and transported in epithelial cells in both a temperature- and a pH-dependent manner, although to a lesser extent than celiprolol. Consistent with the observations in rats, transport of celiprolol from the basal-lateral to the apical side was found to dominate apical-to-basal transport using human Caco-2 cell monolayers. Additionally, using isolated rat small intestinal epithelial cells, celiprolol was found also to have a time- and temperature-dependent uptake, suggesting the involvement of a carrier-mediated system in its uptake. The uptake was inhibited by 2 mM celiprolol and propranolol and was also found to be pH dependent. Saturation of the carrier-mediated secretion of celiprolol in the intestine may result in enhanced absorption of celiprolol at high doses and account for its observed nonlinear absorption.
Kuo
S M
SM
Department of Drug Disposition, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426.
Whitby
B R
BR
Artursson
P
P
Ziemniak
J A
JA
D000818:Animals; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D017272:Celiprolol / Q000493:pharmacokinetics*; D002460:Cell Line; D004386:Duodenum; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D011433:Propranolol / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D011433:Propranolol; D017272:Celiprolol