PT - JOURNAL ARTICLE AU - Robert W. Busby AU - Marco M. Kessler AU - Wilmin P. Bartolini AU - Alexander P. Bryant AU - Gerhard Hannig AU - Carolyn S. Higgins AU - Robert M. Solinga AU - Jenny V. Tobin AU - James D. Wakefield AU - Caroline B. Kurtz AU - Mark G. Currie TI - 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 AID - 10.1124/jpet.112.199430 DP - 2013 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 196--206 VI - 344 IP - 1 4099 - http://jpet.aspetjournals.org/content/344/1/196.short 4100 - http://jpet.aspetjournals.org/content/344/1/196.full SO - J Pharmacol Exp Ther2013 Jan 01; 344 AB - 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.