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

Linaclotide, a potent guanylate cyclase C agonist, is a therapeu-tic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idio-pathic constipation. We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and hu-mans. We examined the metabolic stability of linaclotide in con-ditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which con-tributes 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 converte