B J Aungst1, H Saitoh. 1. Dupont Merck Research Laboratories, Wilmington, Delaware 19880-0400, USA.
Abstract
PURPOSE: The intestinal absorption of DMP 728, a cyclic peptide fibrinogen antagonist, was examined with the goals of identifying the cause(s) of its low oral bioavailability and understanding the mechanisms of its intestinal transport. METHODS: In vitro partitioning, metabolism, and permeation through rat intestinal segments were evaluated. RESULTS: DMP 728 had low lipophilicity and low intestinal permeation rates relative to model compounds. In addition, DMP 728 in vitro intestinal permeation in the secretory direction greatly exceeded transport in the absorptive direction. The secretory transport was saturable, glucose-dependent, and was inhibited by verapamil and by a monoclonal antibody to P-glycoprotein. DMP 728 likewise inhibited the secondary transport of verapamil. Mucosal-to-serosal permeation rates increased in going from the proximal to distal intestinal sites, but were lower than serosal-to-mucosal permeation rates for each site. CONCLUSIONS: Net secretory transport and low lipophilicity are the major barriers to absorption of DMP 728.
PURPOSE: The intestinal absorption of DMP 728, a cyclic peptide fibrinogen antagonist, was examined with the goals of identifying the cause(s) of its low oral bioavailability and understanding the mechanisms of its intestinal transport. METHODS: In vitro partitioning, metabolism, and permeation through rat intestinal segments were evaluated. RESULTS:DMP 728 had low lipophilicity and low intestinal permeation rates relative to model compounds. In addition, DMP 728 in vitro intestinal permeation in the secretory direction greatly exceeded transport in the absorptive direction. The secretory transport was saturable, glucose-dependent, and was inhibited by verapamil and by a monoclonal antibody to P-glycoprotein. DMP 728 likewise inhibited the secondary transport of verapamil. Mucosal-to-serosal permeation rates increased in going from the proximal to distal intestinal sites, but were lower than serosal-to-mucosal permeation rates for each site. CONCLUSIONS: Net secretory transport and low lipophilicity are the major barriers to absorption of DMP 728.
Authors: S A Mousa; J M Bozarth; M S Forsythe; S M Jackson; A Leamy; M M Diemer; R P Kapil; R M Knabb; M C Mayo; S K Pierce Journal: Circulation Date: 1994-01 Impact factor: 29.690
Authors: W Kamm; J Hauptmann; I Behrens; J Stürzebecher; F Dullweber; H Gohlke; M Stubbs; G Klebe; T Kissel Journal: Pharm Res Date: 2001-08 Impact factor: 4.200