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Linaclotide Pharmacodynamics

Robert W. Busby PhD

To the Editor:

We read with great interest the Drug Forecast article in the March 2013 issue of P&T by Dr. Rachel Hutchins Thomas and Mr. Kyle Allmond entitled “Linaclotide (Linzess) for Irritable Bowel Syndrome with Constipation and for Chronic Idiopathic Constipation.”1 We thank the authors for their thorough and balanced review of linaclotide. We noted some technical inaccuracies in the summary of pharmacodynamics that merit attention and wish to provide clarification on these matters.

Both linaclotide and its metabolite are active peptides. As Thomas and Allmond accurately describe, linaclotide and its metabolite act locally within the gastrointestinal (GI) tract.2 However, the statement that “linaclotide and its metabolite are activated by oxidation in the GI tract” is factually inaccurate. Linaclotide is not a prodrug and needs no biochemical activation. Both linaclotide and its metabolite are potent agonists of guanylate cyclase-C (GC-C); they act from within the lumen of the GI tract and neither peptide is “activated by oxidation.”3,4

Linaclotide is more potent than guanylin or uroguanylin. Citing Busby et al.,3 Thomas and Allmond summarize the potency of linaclotide as compared to guanylin and uroguanylin. But as stated, the relationship is inverted. The concentration of linaclotide required to produce 50% of maximal activity (EC50) is eight-fold to ten-fold less than that of guanylin and uroguanylin at pH7. In other words, linaclotide is eight-fold to ten-fold more potent than guanylin or uroguanylin.3

Again, we appreciate the authors’ extensive review of linaclotide pharmacology and the clinical studies in irritable bowel syndrome with constipation and chronic idiopathic constipation. We hope that our clarification of the pharmacodynamics of the drug will serve your readership and help to ensure the appropriate use of linaclotide.


Robert W. Busby, PhD
Vice President, Analytical Pharmacology/Drug Metabolism & Pharmacokinetics
Ironwood Pharmaceuticals, Inc.
301 Binney Street
Cambridge MA 02142
George Zhang, PhD
Senior Principal Scientist
Forest Research Institute, Inc.
Harborside Financial Center, Plaza V
Jersey City, NJ 07311
  • Thomas R, Allmond K. Linaclotide (Linzess) for irritable bowel syndrome with constipation and for chronic idiopathic constipation. P&T 2013;38;(3):154–160.
  • Linzess (linaclotide), prescribing information St. Louis: Forest Pharmaceuticals, Inc.. 2012;
  • Busby RW, Bryant AP, Bartolini WP, et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol 2010;649:328–335.
  • Busby RW, Kessler MM, Bartolini WP, et al. 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. J Pharmacol Exp Ther 2013;344;(1):196–206.