Modulation of intestinal permeability by nitric oxide donors: Implications in intestinal delivery of poorly absorbable drugs

Akira Yamamoto, Hiroyuki Tatsumi, Masato Maruyama, Tomomi Uchiyama, Naoki Okada, Takuya Fujita

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

The effects of nitric oxide (NO) donors NOC5 [3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine] and NOC12 [N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine] on the permeability of 5(6)-carboxyfluorescein (CF) across the intestinal membrane were examined by an in vitro using chamber method. The NO donors significantly increased the intestinal permeability of CF and their absorption-enhancing effects were concentration-dependent over the range of 0.01 to 0.1 mM. Regional differences in the absorption-enhancing effects of the NO donors were observed (colon > jejunum). The absorption-enhancing effect of NOC12 reduced as the molecular weights of compounds increased. Therefore, the degree of absorption-enhancing effect of NOC12 was dependent on the molecular weights of compounds. In the pretreatment studies with NOC12 and lactate dehydrogenase release studies, the absorption-enhancing effect of 0.1 mM NOC12 was reversible and less toxic to the colonic membrane. On the other hand, the absorption-enhancing effect of NOC12 was inhibited by the coadministration of 2-(4-carboxyphenyl) 4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide sodium salt, an NO scavenger, suggesting that NO can regulate the permeability of water-soluble drugs in the gut. Furthermore, NOC12 (0.1 and 1 mM) significantly decreased the transepithelial electrical resistance value of the colonic membrane, suggesting that the absorptionenhancing mechanism of NOC12 may be partly related to the dilation of the tight junction in the epithelium via a paracellular route. These findings suggest that NO donors may be useful to enhance the intestinal absorption of poorly absorbable drugs.

Original languageEnglish
Pages (from-to)84-90
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume296
Issue number1
Publication statusPublished - Jan 11 2001
Externally publishedYes

Fingerprint

Nitric Oxide Donors
Permeability
Pharmaceutical Preparations
Membranes
Nitric Oxide
Molecular Weight
Tight Junctions
Poisons
Intestinal Absorption
Jejunum
Electric Impedance
L-Lactate Dehydrogenase
Dilatation
Colon
Epithelium
Salts
Water

ASJC Scopus subject areas

  • Pharmacology

Cite this

Modulation of intestinal permeability by nitric oxide donors : Implications in intestinal delivery of poorly absorbable drugs. / Yamamoto, Akira; Tatsumi, Hiroyuki; Maruyama, Masato; Uchiyama, Tomomi; Okada, Naoki; Fujita, Takuya.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 296, No. 1, 11.01.2001, p. 84-90.

Research output: Contribution to journalArticle

Yamamoto, Akira ; Tatsumi, Hiroyuki ; Maruyama, Masato ; Uchiyama, Tomomi ; Okada, Naoki ; Fujita, Takuya. / Modulation of intestinal permeability by nitric oxide donors : Implications in intestinal delivery of poorly absorbable drugs. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 296, No. 1. pp. 84-90.
@article{066fa178372447abb6ea17b9ca60ffc9,
title = "Modulation of intestinal permeability by nitric oxide donors: Implications in intestinal delivery of poorly absorbable drugs",
abstract = "The effects of nitric oxide (NO) donors NOC5 [3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine] and NOC12 [N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine] on the permeability of 5(6)-carboxyfluorescein (CF) across the intestinal membrane were examined by an in vitro using chamber method. The NO donors significantly increased the intestinal permeability of CF and their absorption-enhancing effects were concentration-dependent over the range of 0.01 to 0.1 mM. Regional differences in the absorption-enhancing effects of the NO donors were observed (colon > jejunum). The absorption-enhancing effect of NOC12 reduced as the molecular weights of compounds increased. Therefore, the degree of absorption-enhancing effect of NOC12 was dependent on the molecular weights of compounds. In the pretreatment studies with NOC12 and lactate dehydrogenase release studies, the absorption-enhancing effect of 0.1 mM NOC12 was reversible and less toxic to the colonic membrane. On the other hand, the absorption-enhancing effect of NOC12 was inhibited by the coadministration of 2-(4-carboxyphenyl) 4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide sodium salt, an NO scavenger, suggesting that NO can regulate the permeability of water-soluble drugs in the gut. Furthermore, NOC12 (0.1 and 1 mM) significantly decreased the transepithelial electrical resistance value of the colonic membrane, suggesting that the absorptionenhancing mechanism of NOC12 may be partly related to the dilation of the tight junction in the epithelium via a paracellular route. These findings suggest that NO donors may be useful to enhance the intestinal absorption of poorly absorbable drugs.",
author = "Akira Yamamoto and Hiroyuki Tatsumi and Masato Maruyama and Tomomi Uchiyama and Naoki Okada and Takuya Fujita",
year = "2001",
month = "1",
day = "11",
language = "English",
volume = "296",
pages = "84--90",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Modulation of intestinal permeability by nitric oxide donors

T2 - Implications in intestinal delivery of poorly absorbable drugs

AU - Yamamoto, Akira

AU - Tatsumi, Hiroyuki

AU - Maruyama, Masato

AU - Uchiyama, Tomomi

AU - Okada, Naoki

AU - Fujita, Takuya

PY - 2001/1/11

Y1 - 2001/1/11

N2 - The effects of nitric oxide (NO) donors NOC5 [3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine] and NOC12 [N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine] on the permeability of 5(6)-carboxyfluorescein (CF) across the intestinal membrane were examined by an in vitro using chamber method. The NO donors significantly increased the intestinal permeability of CF and their absorption-enhancing effects were concentration-dependent over the range of 0.01 to 0.1 mM. Regional differences in the absorption-enhancing effects of the NO donors were observed (colon > jejunum). The absorption-enhancing effect of NOC12 reduced as the molecular weights of compounds increased. Therefore, the degree of absorption-enhancing effect of NOC12 was dependent on the molecular weights of compounds. In the pretreatment studies with NOC12 and lactate dehydrogenase release studies, the absorption-enhancing effect of 0.1 mM NOC12 was reversible and less toxic to the colonic membrane. On the other hand, the absorption-enhancing effect of NOC12 was inhibited by the coadministration of 2-(4-carboxyphenyl) 4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide sodium salt, an NO scavenger, suggesting that NO can regulate the permeability of water-soluble drugs in the gut. Furthermore, NOC12 (0.1 and 1 mM) significantly decreased the transepithelial electrical resistance value of the colonic membrane, suggesting that the absorptionenhancing mechanism of NOC12 may be partly related to the dilation of the tight junction in the epithelium via a paracellular route. These findings suggest that NO donors may be useful to enhance the intestinal absorption of poorly absorbable drugs.

AB - The effects of nitric oxide (NO) donors NOC5 [3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine] and NOC12 [N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine] on the permeability of 5(6)-carboxyfluorescein (CF) across the intestinal membrane were examined by an in vitro using chamber method. The NO donors significantly increased the intestinal permeability of CF and their absorption-enhancing effects were concentration-dependent over the range of 0.01 to 0.1 mM. Regional differences in the absorption-enhancing effects of the NO donors were observed (colon > jejunum). The absorption-enhancing effect of NOC12 reduced as the molecular weights of compounds increased. Therefore, the degree of absorption-enhancing effect of NOC12 was dependent on the molecular weights of compounds. In the pretreatment studies with NOC12 and lactate dehydrogenase release studies, the absorption-enhancing effect of 0.1 mM NOC12 was reversible and less toxic to the colonic membrane. On the other hand, the absorption-enhancing effect of NOC12 was inhibited by the coadministration of 2-(4-carboxyphenyl) 4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide sodium salt, an NO scavenger, suggesting that NO can regulate the permeability of water-soluble drugs in the gut. Furthermore, NOC12 (0.1 and 1 mM) significantly decreased the transepithelial electrical resistance value of the colonic membrane, suggesting that the absorptionenhancing mechanism of NOC12 may be partly related to the dilation of the tight junction in the epithelium via a paracellular route. These findings suggest that NO donors may be useful to enhance the intestinal absorption of poorly absorbable drugs.

UR - http://www.scopus.com/inward/record.url?scp=0035198046&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035198046&partnerID=8YFLogxK

M3 - Article

C2 - 11123366

AN - SCOPUS:0035198046

VL - 296

SP - 84

EP - 90

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -