Linaclotide
Linaclotide. GC-C (guanylate cyclase-C) agonist — raises intestinal cGMP → CFTR-mediated chloride / bicarbonate / water secretion into lumen. Approved for chronic…
GC-C (guanylate cyclase-C) agonist — raises intestinal cGMP → CFTR-mediated chloride / bicarbonate / water secretion into lumen. Approved for chronic idiopathic constipation + IBS-C. Minimal systemic absorption → DDI-light. Diarrhea is the main dose-limiting side effect.
PK REMOVED. ITS LABEL NAMES THIS RECORD EXACT DOSE TRIPLE AS UNMEASURABLE: "Concentrations of linaclotide and its active metabolite in plasma are BELOW THE LIMIT OF QUANTITATION after oral doses of 72 mcg, 145 mcg, or 290 mcg" and "minimally absorbed with negligible systemic availability" — and the registry doses are those same three. The stored parameters drew a curve peaking around nine picograms per millilitre, roughly twenty times below any published assay limit, FOR A QUANTITY NEVER MEASURED IN A HUMAN, so the volume is not merely unsourced but unmeasurable in principle. The stored bioavailability of 0.1% is also the WRONG SPECIES: its source is preclinical throughout and never attaches a species to that figure, while the companion disposition paper settles it — "the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in THE RAT confirmed both peptides are minimally absorbed". This is a fourteen-amino-acid peptide acting on guanylate cyclase-C at the apical surface of enterocytes; the lumen is the compartment that matters.
Sources: PMID:20863829, PMID:23090647