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

• DOI: 10.1021/acs.molpharmaceut.1c00309
• Publication Date: 2021-07-13T18:35:28Z
• Authors: Tahnee J. Dening; Justin T. Douglas; Michael J. Hageman
• Keywords: 0301 basic medicine; Intestinal Secretions; Biological Availability; Water; Membranes, Artificial; Octreotide; Bile Acids and Salts; Solutions; 03 medical and health sciences; 0302 clinical medicine; Intestinal Absorption; Solubility; Pancreatin; Deamino Arginine Vasopressin; Colloids; Intestinal Mucosa; Cellulose; Micelles; Phospholipids; Half-Life

Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, direct interaction between various biorelevant colloids (i.e., bile salt micelles salt-phospholipid mixed micelles) present aqueous environment peptide drug molecules has not been studied. In this work, we systematically characterized interactions a water-soluble model drug, octreotide, range of physiologically relevant salts solution. Octreotide flux pure solutions commercially available media, i.e., fasted state simulated intestinal fluid (FaSSIF) fed (FeSSIF), was evaluated using side-by-side diffusion cell equipped with cellulose dialysis membrane. All seven micellar as well FaSSIF FeSSIF decreased octreotide flux, dihydroxy were found have much larger effect than trihydroxy salts. An inverse relationship pancreatic stability also observed; provided protective toward prolonged half-life vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy dynamic light scattering (DLS) used complementary experimental techniques confirm peptide-micelle Experiments performed desmopressin second drug; interacted solution, albeit lower extent relative octreotide. The findings described herein demonstrate that amphiphilic, do interact phospholipids an on stability. Correspondingly, absorption bioavailability may be impacted.