title: In vivo non-linear intestinal permeability of celiprolol and propranolol in conscious dogs: evidence for intestinal secretion.
abstract: The objective of this study was to investigate the absorption mechanism of celiprolol as a potential source of the drug's non-linear oral pharmacokinetics by determining its intestinal permeability as a function 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 analyzed by an enantioselective HPLC method (Hartmann et al., J. Chromatogr., 496 (1989) 387-396). Permeability (P(eff) x 10(4) cm/s) of celiprolol 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 significantly with increasing celiprolol concentrations, suggesting that propranolol 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.
authors.affiliation: College of Pharmacy, The University of Michigan, Ann Arbor 48109-1065, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lipka
authors.forename: H
authors.initials: H
authors.lastname: Spahn-Langguth
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: G L
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D000818:Animals; D017272:Celiprolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003243:Consciousness; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007408:Intestinal Absorption; D007419:Intestinal Secretions; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010539:Permeability; D011433:Propranolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D014665:Vasodilator Agents; D011433:Propranolol; D017272:Celiprolol