Intestinal absorption barriers and transport mechanisms, including secretory transport, for a cyclic peptide, fibrinogen antagonist.
OBJECTIVE
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.
Aungst
B J
BJ
Dupont Merck Research Laboratories, Wilmington, Delaware 19880-0400, USA.
Saitoh
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005340:Fibrinogen / Q000037:antagonists & inhibitors*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008698:Mesylates / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D008698:Mesylates; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D011522:Protons; C085286:DMP 728; D005340:Fibrinogen; D014700:Verapamil