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Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine

As advanced synthetic technology has enabled drug candidate development with complex structure, resulting in low solubility and membrane permeability, the strategies to improve poorly absorbed drug bioavailability have attracted the attention of pharmaceutical companies. It has been demonstrated tha...

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Autores principales: Kishimoto, Hisanao, Miyazaki, Kaori, Tedzuka, Hiroshi, Ozawa, Ryosuke, Kobayashi, Hanai, Shirasaka, Yoshiyuki, Inoue, Katsuhisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587071/
https://www.ncbi.nlm.nih.gov/pubmed/34770805
http://dx.doi.org/10.3390/molecules26216396
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author Kishimoto, Hisanao
Miyazaki, Kaori
Tedzuka, Hiroshi
Ozawa, Ryosuke
Kobayashi, Hanai
Shirasaka, Yoshiyuki
Inoue, Katsuhisa
author_facet Kishimoto, Hisanao
Miyazaki, Kaori
Tedzuka, Hiroshi
Ozawa, Ryosuke
Kobayashi, Hanai
Shirasaka, Yoshiyuki
Inoue, Katsuhisa
author_sort Kishimoto, Hisanao
collection PubMed
description As advanced synthetic technology has enabled drug candidate development with complex structure, resulting in low solubility and membrane permeability, the strategies to improve poorly absorbed drug bioavailability have attracted the attention of pharmaceutical companies. It has been demonstrated that nitric oxide (NO), a vital signaling molecule that plays an important role in various physiological systems, affects intestinal drug absorption. However, NO and its oxidants are directly toxic to the gastrointestinal tract, thereby limiting their potential clinical application as absorption enhancers. In this study, we show that sodium nitroprusside (SNP), an FDA-approved vasodilator, enhances the intestinal absorption of lipophilic drugs in the proximal parts of the small intestine in rats. The SNP pretreatment of the rat gastrointestinal sacs significantly increased griseofulvin and flurbiprofen permeation in the duodenum and jejunum but not in the ileum and colon. These SNP-related enhancement effects were attenuated by the co-pretreatment with dithiothreitol or c-PTIO, an NO scavenger. The permeation-enhancing effects were not observed in the case of antipyrine, theophylline, and propranolol in the duodenum and jejunum. Furthermore, the SNP treatment significantly increased acidic glycoprotein release from the mucosal layers specifically in the duodenum and jejunum but not in the ileum and colon. These results suggest that SNP increases lipophilic drug membrane permeability specifically in the proximal region of the small intestine through disruption of the mucosal layer.
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spelling pubmed-85870712021-11-13 Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine Kishimoto, Hisanao Miyazaki, Kaori Tedzuka, Hiroshi Ozawa, Ryosuke Kobayashi, Hanai Shirasaka, Yoshiyuki Inoue, Katsuhisa Molecules Article As advanced synthetic technology has enabled drug candidate development with complex structure, resulting in low solubility and membrane permeability, the strategies to improve poorly absorbed drug bioavailability have attracted the attention of pharmaceutical companies. It has been demonstrated that nitric oxide (NO), a vital signaling molecule that plays an important role in various physiological systems, affects intestinal drug absorption. However, NO and its oxidants are directly toxic to the gastrointestinal tract, thereby limiting their potential clinical application as absorption enhancers. In this study, we show that sodium nitroprusside (SNP), an FDA-approved vasodilator, enhances the intestinal absorption of lipophilic drugs in the proximal parts of the small intestine in rats. The SNP pretreatment of the rat gastrointestinal sacs significantly increased griseofulvin and flurbiprofen permeation in the duodenum and jejunum but not in the ileum and colon. These SNP-related enhancement effects were attenuated by the co-pretreatment with dithiothreitol or c-PTIO, an NO scavenger. The permeation-enhancing effects were not observed in the case of antipyrine, theophylline, and propranolol in the duodenum and jejunum. Furthermore, the SNP treatment significantly increased acidic glycoprotein release from the mucosal layers specifically in the duodenum and jejunum but not in the ileum and colon. These results suggest that SNP increases lipophilic drug membrane permeability specifically in the proximal region of the small intestine through disruption of the mucosal layer. MDPI 2021-10-22 /pmc/articles/PMC8587071/ /pubmed/34770805 http://dx.doi.org/10.3390/molecules26216396 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kishimoto, Hisanao
Miyazaki, Kaori
Tedzuka, Hiroshi
Ozawa, Ryosuke
Kobayashi, Hanai
Shirasaka, Yoshiyuki
Inoue, Katsuhisa
Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine
title Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine
title_full Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine
title_fullStr Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine
title_full_unstemmed Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine
title_short Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine
title_sort utilization of sodium nitroprusside as an intestinal permeation enhancer for lipophilic drug absorption improvement in the rat proximal intestine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587071/
https://www.ncbi.nlm.nih.gov/pubmed/34770805
http://dx.doi.org/10.3390/molecules26216396
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