Intestinal Absorption Barriers and Transport Mechanisms, Including Secretory Transport, for a Cyclic Peptide, Fibrinogen Antagonist

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 1996 Jan 1

PMID 8668658

Citations 6

Authors

B J Aungst

H Saitoh

Affiliations

Soon will be listed here.

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.

Citing Articles

Transport of peptidomimetic thrombin inhibitors with a 3-amidino-phenylalanine structure: permeability and efflux mechanism in monolayers of a human intestinal cell line (Caco-2).

KAMM W, Hauptmann J, Behrens I, Sturzebecher J, Dullweber F, Gohlke H Pharm Res. 2001; 18(8):1110-8.

PMID: 11587481 DOI: 10.1023/a:1010966708181.

Improvement of the intestinal absorption of a peptidomimetic, boronic acid thrombin inhibitor possibly utilizing the oligopeptide transporter.

Saitoh H, Aungst B Pharm Res. 1999; 16(11):1786-9.

PMID: 10571288 DOI: 10.1023/a:1011989504054.

Prodrug approach for alphaIIbbeta3-peptidomimetic antagonists to enhance their transport in monolayers of a human intestinal cell line (Caco-2): comparison of in vitro and in vivo data.

KAMM W, Raddatz P, Gante J, Kissel T Pharm Res. 1999; 16(10):1527-33.

PMID: 10554093 DOI: 10.1023/a:1015044318650.

Drug exsorption from blood into the gastrointestinal tract.

Arimori K, Nakano M Pharm Res. 1998; 15(3):371-6.

PMID: 9563065 DOI: 10.1023/a:1011959828103.

Prodrug and analog approaches to improving the intestinal absorption of a cyclic peptide, GPIIb/IIIa receptor antagonist.

Saitoh H, Aungst B Pharm Res. 1997; 14(8):1026-9.

PMID: 9279884 DOI: 10.1023/a:1012149227756.

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