IN-VIVO NONLINEAR INTESTINAL PERMEABILITY OF CELIPROLOL AND PROPRANOLOL IN CONSCIOUS DOGS - EVIDENCE FOR INTESTINAL SECRETION

The objective of this study was to investigate the absorption mechanis m of celiprolol as a potential source of the drug's non-linear oral ph armacokinetics by determining its intestinal permeability as a functio n of concentration in vivo in dogs. Solutions of different celiprolol concentrations containing propranolol as an internal absorption marker were perfused through an isolated jejunal segment and samples were an alyzed by an enantioselective HPLC method (Hartmann et al., J. Chromat ogr, 496 (1989) 387-396). Permeability (P-eff x 10(4) cm/s) of celipro lol increased significantly from 1.9-2.1 for the lower concentrations to 3.2 for the highest concentration, while the variability decreased. No statistical differences in the uptake between the two enantiomers were observed. Permeability of propranolol also increased significantl y with increasing celiprolol concentrations, suggesting that propranol ol might be utilizing the same carrier protein. In conclusion, the non -linear and variable oral pharmacokinetics of celiprolol might be due to a non-linear saturable, possibly secretion component in its uptake mechanism. (C) 1998 Elsevier Science B.V.