Abstract | AIMS: MAIN METHODS:
Linaclotide binding to intestinal mucosal membranes was assessed in competitive binding assays. Stability and oral bioavailability of linaclotide were measured in small intestinal fluid and serum, respectively, and models of gastrointestinal function were conducted using wild type (wt) and GC-C null mice. KEY FINDINGS:
Linaclotide inhibited in vitro [(125)I]-STa binding to intestinal mucosal membranes from wt mice in a concentration-dependent manner. In contrast, [(125)I]-STa binding to these membranes from GC-C null mice was significantly decreased. After incubation in vitro in jejunal fluid for 30 min, linaclotide was completely degraded. Pharmacokinetic analysis showed very low oral bioavailability (0.10%). In intestinal secretion and transit models, linaclotide exhibited significant pharmacological effects in wt, but not in GC-C null mice: induction of increased fluid secretion into surgically ligated jejunal loops was accompanied by the secretion of elevated levels of cyclic guanosine-3',5'-monophosphate and accelerated gastrointestinal transit. SIGNIFICANCE:
Linaclotide is a potent and selective GC-C agonist that elicits pharmacological effects locally in the gastrointestinal tract. This pharmacological profile suggests that orally administered linaclotide may be capable of improving the abdominal symptoms and bowel habits of patients suffering from IBS-C and chronic constipation.
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Authors | Alexander P Bryant, Robert W Busby, Wilmin P Bartolini, Etchell A Cordero, Gerhard Hannig, Marco M Kessler, Christine M Pierce, Robert M Solinga, Jenny V Tobin, Shalina Mahajan-Miklos, Mitchell B Cohen, Caroline B Kurtz, Mark G Currie |
Journal | Life sciences
(Life Sci)
Vol. 86
Issue 19-20
Pg. 760-5
(May 08 2010)
ISSN: 1879-0631 [Electronic] Netherlands |
PMID | 20307554
(Publication Type: Journal Article)
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Copyright | Copyright 2010 Elsevier Inc. All rights reserved. |
Chemical References |
- Gastrointestinal Agents
- Peptides
- Receptors, Peptide
- Guanylate Cyclase
- Gucy2c protein, mouse
- Receptors, Enterotoxin
- Receptors, Guanylate Cyclase-Coupled
- linaclotide
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Topics |
- Administration, Oral
- Animals
- Biological Availability
- Dose-Response Relationship, Drug
- Female
- Gastrointestinal Agents
(administration & dosage, pharmacokinetics, pharmacology)
- Gastrointestinal Tract
(drug effects, metabolism)
- Gastrointestinal Transit
(drug effects)
- Guanylate Cyclase
(genetics)
- Intestinal Mucosa
(metabolism)
- Intestinal Secretions
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Peptides
(administration & dosage, pharmacokinetics, pharmacology)
- Receptors, Enterotoxin
- Receptors, Guanylate Cyclase-Coupled
- Receptors, Peptide
(agonists, genetics)
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