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The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin

Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objectiv...

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Autores principales: Dahlgren, David, Sjöblom, Markus, Hedeland, Mikael, Lennernäs, Hans
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076382/
https://www.ncbi.nlm.nih.gov/pubmed/31991924
http://dx.doi.org/10.3390/pharmaceutics12020099
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author Dahlgren, David
Sjöblom, Markus
Hedeland, Mikael
Lennernäs, Hans
author_facet Dahlgren, David
Sjöblom, Markus
Hedeland, Mikael
Lennernäs, Hans
author_sort Dahlgren, David
collection PubMed
description Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs.
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spelling pubmed-70763822020-03-24 The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin Dahlgren, David Sjöblom, Markus Hedeland, Mikael Lennernäs, Hans Pharmaceutics Article Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs. MDPI 2020-01-26 /pmc/articles/PMC7076382/ /pubmed/31991924 http://dx.doi.org/10.3390/pharmaceutics12020099 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dahlgren, David
Sjöblom, Markus
Hedeland, Mikael
Lennernäs, Hans
The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin
title The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin
title_full The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin
title_fullStr The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin
title_full_unstemmed The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin
title_short The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin
title_sort in vivo effect of transcellular permeation enhancers on the intestinal permeability of two peptide drugs enalaprilat and hexarelin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076382/
https://www.ncbi.nlm.nih.gov/pubmed/31991924
http://dx.doi.org/10.3390/pharmaceutics12020099
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