Do Macrocyclic Peptide Drugs Interact with Bile Salts under Simulated Gastrointestinal Conditions?

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 101197791 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1543-8392 (Electronic) Linking ISSN: 15438384 NLM ISO Abbreviation: Mol Pharm Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Chemical Society, c2004-
    • Subject Terms:
      Bile Acids and Salts/*metabolism ; Deamino Arginine Vasopressin/*metabolism ; Intestinal Mucosa/*metabolism ; Intestinal Secretions/*metabolism ; Octreotide/*metabolism; Biological Availability ; Cellulose ; Colloids/metabolism ; Deamino Arginine Vasopressin/pharmacokinetics ; Half-Life ; Intestinal Absorption/drug effects ; Membranes, Artificial ; Micelles ; Octreotide/chemistry ; Octreotide/pharmacokinetics ; Pancreatin/metabolism ; Phospholipids/metabolism ; Solubility ; Solutions ; Water/chemistry
    • Abstract:
      Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed; bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug; desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that amphiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.
    • Contributed Indexing:
      Keywords: FaSSIF; FeSSIF; bile salt; desmopressin; octreotide; peptide drug
    • Accession Number:
      0 (Bile Acids and Salts)
      0 (Colloids)
      0 (Membranes, Artificial)
      0 (Micelles)
      0 (Phospholipids)
      0 (Solutions)
      059QF0KO0R (Water)
      8049-47-6 (Pancreatin)
      9004-34-6 (Cellulose)
      ENR1LLB0FP (Deamino Arginine Vasopressin)
      RWM8CCW8GP (Octreotide)
    • Publication Date:
      Date Created: 20210713 Date Completed: 20220120 Latest Revision: 20220120
    • Publication Date:
      20221213
    • Accession Number:
      10.1021/acs.molpharmaceut.1c00309
    • Accession Number:
      34255531