Pharmacology Plecanatide

1 pharmacology

1.1 structure , function
1.2 mechanism of action
1.3 pharmacokinetics , metabolism

pharmacology
structure , function

plecanatide 16 amino acid peptide amino acid sequence:

h-asn-asp-glu-cys-glu-leu-cys-val-asn-val-ala-cys-thr-gly-cys-leu-oh

is structurally identical human uroguanylin, apart substitution of asp glu. disulphide bonds exist between cys , cys, cys , cys.

plecanatide has 2 important motifs. first being acidic residues asp , glu modulate affinity receptor in response environmental ph. simulations predict optimal activity of plecanatide occur @ ph 5, making suitable targeting cells within proximal intestine, has ph of between 5 , 6. second actgc motif (residues ala cys) region responsible binding receptor, guanylate cyclase-c.

mechanism of action

plecanatide works laxative drawing water in gastrointestinal tract thereby softening stool , encouraging natural passage.

similar endogenous counterpart, plecanatide activates guanylate cyclase-c on endothelial cells within gastrointestinal tract. activation of guanylate cyclase-c catalyses production of second messenger guanosine 3’,5’-cyclic monophosphate (cgmp) leads protein kinase (pka) , protein kinase g ii (pkgii)-mediated phosphorylation of cystic fibrosis transmembrane conductance regulator (cftr) protein. cftr anion channel , upon activation secrete negatively charged ions, particularly chloride (cl) , bicarbonate (hco3) in gi tract lumen. disruption electrochemical gradient in part rectified passive secretion of positively charged sodium ions in lumen , water follows osmosis.

plecanatide known have anti-nociceptive effect in animal models, exact mechanism of action not yet elucidated. has been suggested may in part anti-inflammatory action of guanylate cyclase-c inhibition of pro-inflammatory cytokines, or through inhibition of associated sensory neurons.

pharmacokinetics , metabolism

as plecanatide acts on receptors present on apical side of endothelial cells lining gastrointestinal tract able impart effect without ever entering circulation. orally ingested peptides, plecanatide degraded intestinal enzymes , little of active drug enters systemic circulation. minimal amounts of drug expected transported in body , concentrations of plecanatide , metabolites undetectable in plasma following recommended dosage of 3 mg. has been shown dosages 48.6 mg produced no detectable concentration of plecanatide in human plasma @ time point after ingestion.