Abstract
Linaclotide, a potent guanylate cyclase C agonist, is an investigational peptide in development for the treatment of irritable bowel syndrome with constipation and chronic constipation. In this report, we present 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 investigated the only pharmacologically active metabolite, MM-419447, both in vitro and in vivo. 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 following 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, and then both peptides are proteolyzed. Following 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 cGMP. In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intra-luminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. Together, our experiments show that orally administered linaclotide is proteolyzed in the intestine, forming MM-419447 in the process, which contributes to the pharmacological effects of linaclotide.
- Received August 21, 2012.
- Revision received October 8, 2012.
- Accepted October 19, 2012.
- The American Society for Pharmacology and Experimental Therapeutics