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

Citation
A. Yamamoto et al., Modulation of intestinal permeability by nitric oxide donors: Implicationsin intestinal delivery of poorly absorbable drugs, J PHARM EXP, 296(1), 2001, pp. 84-90
Citations number
29
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
296
Issue
1
Year of publication
2001
Pages
84 - 90
Database
ISI
SICI code
0022-3565(200101)296:1<84:MOIPBN>2.0.ZU;2-A
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)-carboxyfluoresce in (CF) across the intestinal membrane were examined by an in vitro Ussing chamber method. The NO donors significantly increased the intestinal permea bility of CF and their absorption-enhancing effects were concentration-depe ndent over the range of 0.01 to 0.1 mM. Regional differences in the absorpt ion-enhancing effects of the NO donors were observed (colon. jejunum). The absorption-enhancing effect of NOC12 reduced as the molecular weights of co mpounds increased. Therefore, the degree of absorption-enhancing effect of NOC12 was dependent on the molecular weights of compounds. In the pretreatm ent studies with NOC12 and lactate dehydrogenase release studies, the absor ption-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 NO C12 was inhibited by the coadministration of 2-(4-carboxyphenyl) 4,4,5,5-te tramethylimidazole- 1-oxyl 3-oxide sodium salt, an NO scavenger, suggesting that NO can regulate the permeability of water-soluble drugs in the gut. F urthermore, NOC12 (0.1 and 1 mM) significantly decreased the transepithelia l electrical resistance value of the colonic membrane, suggesting that the absorption-enhancing mechanism of NOC12 may be partly related to the dilati on of the tight junction in the epithelium via a paracellular route. These findings suggest that NO donors may be useful to enhance the intestinal abs orption of poorly absorbable drugs.