title: Stability of peptide drugs in the colon.
abstract: This study was the first to investigate the colonic stability of 17 peptide molecules (insulin, calcitonin, glucagon, secretin, somatostatin, desmopressin, oxytocin, Arg-vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, [D-Ser(4)]-gonadorelin, deslorelin, and goserelin) in a model of the large intestine using mixed human faecal bacteria. Of these, the larger peptides - insulin, calcitonin, somatostatin, glucagon and secretin - were metabolized rapidly, with complete degradation observed within 5 min. In contrast, a number of the smaller peptides - Arg-vasopressin, desmopressin, oxytocin, gonadorelin, goserelin, buserelin, leuprolide, nafarelin and deslorelin - degraded more slowly, while octreotide, histrelin and ciclosporin were seen to be more stable as compared to the other small peptides under the same conditions. Peptide degradation rate was directly correlated to peptide lipophilicity (logP); those peptides with a higher logP were more stable in the colonic model (R(2)=0.94). In the absence of human faecal bacteria, all peptides were stable. This study highlights the impact of the colonic environment - in particular, the gut microbiota - on the metabolism of peptide drugs, and identifies potential peptide candidates for drug delivery to the colon.
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, WC1N 1AX London, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, WC1N 1AX London, UK.
authors.forename: Vipul
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, WC1N 1AX London, UK.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Smart
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, WC1N 1AX London, UK.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Tajiri
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, University College London, WC1N 1AX London, UK. Electronic address: a.basit@ucl.ac.uk.
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Basit
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D001419:Bacteria / Q000378:metabolism*; D003106:Colon / Q000378:metabolism* / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D014867:Water / Q000737:chemistry
chemical_list: D010455:Peptides; D014867:Water; D010447:Peptide Hydrolases; D020003:1-Octanol
keywords: Biopharmaceuticals; Colonic delivery; Colonic metabolism; Large intestine; Microbiota; Oral delivery of peptides and proteins