Tahnee J Dening, José G Napolitano, Jessica L Ochoa, Justin T Douglas, Michael J Hageman
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Characterization of macrocyclic peptide drug interactions with bile salts and biorelevant colloids via single amino acid mutations and 1H nuclear magnetic resonance (NMR) spectroscopy.
There is growing interest in the oral delivery of poorly permeable peptide drugs; however, the effect of biorelevant colloids found in the aqueous gastrointestinal environment on peptide drug solution behavior has been largely understudied. In this work, we detail the molecular level interactions between octreotide, a water-soluble macrocyclic peptide drug, and biorelevant colloids, i.e. bile salt micelles and bile salt-phospholipid mixed micelles, via dialysis membrane flux experiments and proton nuclear magnetic resonance (1H NMR) spectroscopy. A modified alanine scan was employed to generate eight mutated octreotide analogs; the impact of individual amino acid mutations on peptide dialysis membrane flux rates in micellar (trihydroxy and dihydroxy) bile salt solutions as well as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) was evaluated and compared against the parent peptide, octreotide. We show that octreotide interacts more strongly with dihydroxy bile salt micelles than trihydroxy bile salt micelles in solution, and in FaSSIF/FeSSIF media, octreotide mainly interacts with the phospholipid component. These interactions are largely mediated by hydrophobic interactions of octreotide's aromatic residues as well as electrostatic interactions between octreotide's basic Lys residue and terminal amine.
期刊介绍:
The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.