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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Pharmacologic Properties, Metabolism, and Disposition of Linaclotide, a Novel Therapeutic Peptide Approved for the Treatment of Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation

Robert W. Busby, Marco M. Kessler, Wilmin P. Bartolini, Alexander P. Bryant, Gerhard Hannig, Carolyn S. Higgins, Robert M. Solinga, Jenny V. Tobin, James D. Wakefield, Caroline B. Kurtz and Mark G. Currie
Journal of Pharmacology and Experimental Therapeutics January 2013, 344 (1) 196-206; DOI: https://doi.org/10.1124/jpet.112.199430
Robert W. Busby
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Marco M. Kessler
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Wilmin P. Bartolini
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Alexander P. Bryant
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Gerhard Hannig
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Carolyn S. Higgins
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Robert M. Solinga
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Jenny V. Tobin
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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James D. Wakefield
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Caroline B. Kurtz
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Mark G. Currie
Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts
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Abstract

Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and humans. We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded. After oral administration of linaclotide, <1% of the dose was excreted as active peptide in rat feces and a mean of 3–5% in human feces; in both cases MM-419447 was the predominant peptide recovered. MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3′,5′-monophosphate (cGMP). In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. These results demonstrate the importance of the active metabolite in contributing to linaclotide’s pharmacology.

Footnotes

  • This study was supported by Ironwood Pharmaceuticals, Inc., of which all the authors are employees and stockholders.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • dx.doi.org/10.1124/jpet.112.199430.

  • Received August 21, 2012.
  • Accepted October 19, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 1
1 Jan 2013
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Pharmacology, Metabolism, and Disposition of Linaclotide

Robert W. Busby, Marco M. Kessler, Wilmin P. Bartolini, Alexander P. Bryant, Gerhard Hannig, Carolyn S. Higgins, Robert M. Solinga, Jenny V. Tobin, James D. Wakefield, Caroline B. Kurtz and Mark G. Currie
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 196-206; DOI: https://doi.org/10.1124/jpet.112.199430

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Pharmacology, Metabolism, and Disposition of Linaclotide

Robert W. Busby, Marco M. Kessler, Wilmin P. Bartolini, Alexander P. Bryant, Gerhard Hannig, Carolyn S. Higgins, Robert M. Solinga, Jenny V. Tobin, James D. Wakefield, Caroline B. Kurtz and Mark G. Currie
Journal of Pharmacology and Experimental Therapeutics January 1, 2013, 344 (1) 196-206; DOI: https://doi.org/10.1124/jpet.112.199430
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