THE CONTRIBUTION OF INTESTINAL SECRETION TO THE DOSE-DEPENDENT ABSORPTION OF CELIPROLOL

The contribution of the intestine to the nonlinear absorption of celip rolol in the rat was studied. After intravenous administration of C-14 -celiprolol to bile duct-cannulated rats, approximately 9% of the dose was found to be associated with intestinal tissue and its contents. M icrohistoautoradiography of frozen intestinal sections showed a time-d ependent 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 epithelia l cells in both a temperature- and a pH-dependent manner, although to a lesser extent than celiprolol. Consistent with the observations in r ats, transport of celiprolol from the basal-lateral to the apical side was found to dominate apical-to-basal transport using human Caco-2 ce ll monolayers. Additionally, using isolated rat small intestinal epith elial cells, celiprolol was found also to have a time- and temperature -dependent uptake, suggesting the involvement of a carrier-mediated sy stem in its uptake. The uptake was inhibited by 2 mM celiprolol and pr opranolol and was also found to be pH dependent. Saturation of the car rier-mediated secretion of celiprolol in the intestine may result in e nhanced absorption of celiprolol at high doses and account for its obs erved nonlinear absorption.