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

Yoshiyuki Shirasaka,Hiroshi Tedzuka,Katsuhisa Inoue,Hanai Kobayashi,Kaori Miyazaki,Ryosuke Ozawa,Hisanao Kishimoto

doi:10.3390/molecules26216396

Yoshiyuki Shirasaka, Hiroshi Tedzuka + Show 5 more

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https://doi.org/10.3390/molecules26216396

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Abstract

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.

Highlights

The development of an improvement approach for the bioavailability of poorly absorbed drugs has been an important challenge in the field of oral drug delivery for decades.The progress in chemical synthesis has enabled the synthesis of molecules with higher molecular weight and complex structures
The nitric oxide (NO)-releasing chemical reagent enhances the absorption of lipophilic drugs in rats, NO and its oxidants are directly toxic to the gastrointestinal tract, thereby limiting their potential clinical application as absorption enhancers [7,16]
We demonstrated that sodium nitroprusside (SNP), a commonly used vasodilator drug for acute heart failure treatments, enhanced the site-specific intestinal permeation of lipophilic drugs in the rat small intestine by removing the mucosal layer

Summary

Introduction

The development of an improvement approach for the bioavailability of poorly absorbed drugs has been an important challenge in the field of oral drug delivery for decades.The progress in chemical synthesis has enabled the synthesis of molecules with higher molecular weight and complex structures. The major problems are generally based on high lipophilicity and low solubility To overcome these problems and to increase the oral bioavailability of these drugs, several types of absorption enhancers, including solvents, chelators, bile salts, surfactants, and polymers have been investigated [1,2]. These absorption enhancers are concomitantly administered with a lipophilic drug to increase its solubility in the gastrointestinal fluid, resulting in an accelerated passive diffusion across the mucosa. These effects are assumed to be nonspecific and cytotoxic, thereby limiting potential clinical applications

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