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 Ussing 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 absorption-enhancing 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.
Footnotes
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Send reprint requests to: Akira Yamamoto, Ph.D., Department of Biopharmaceutics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan. E-mail: yamamoto{at}mb.kyoto-phu.ac.jp
- Abbreviations:
- NaGC
- sodium glycocholate
- NaDC
- sodium deoxycholate
- LM
- n-dodecyl-β-d-maltopyranoside
- NO
- nitric oxide
- LDH
- lactate dehydrogenase
- NOC5
- 3-(2-hydroxy-1-(methylethyl)-2-nitrosohydrazino)-1-propanamine
- NOC12
- N-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-ethanamine
- CF
- 5(6)-carboxyfluorescein
- FD4
- fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4,000
- FD10
- fluorescein isothiocyanate-labeled dextran with an average molecular weight of 10,000
- carboxy-PTIO
- 2-(4-carboxyphenyl) 4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide sodium salt
- NaCap
- sodium caprate
- Papp
- apparent permeability coefficient
- TEER
- transepithelial electrical resistance
- SNAP
- S-nitroso-N-acetyl-penicillamine
- SNP
- sodium nitroprusside
- Received March 2, 2000.
- Accepted September 26, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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