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Modulation of intestinal permeability by nitric oxide donors: implications in intestinal delivery of poorly absorbable drugs.
J Pharmacol Exp Ther. 2001 Jan; 296(1):84-90.JP

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.

Authors+Show Affiliations

Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto, Japan. yamamoto@mb.kyoto-phu.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11123366

Citation

Yamamoto, A, et al. "Modulation of Intestinal Permeability By Nitric Oxide Donors: Implications in Intestinal Delivery of Poorly Absorbable Drugs." The Journal of Pharmacology and Experimental Therapeutics, vol. 296, no. 1, 2001, pp. 84-90.
Yamamoto A, Tatsumi H, Maruyama M, et al. Modulation of intestinal permeability by nitric oxide donors: implications in intestinal delivery of poorly absorbable drugs. J Pharmacol Exp Ther. 2001;296(1):84-90.
Yamamoto, A., Tatsumi, H., Maruyama, M., Uchiyama, T., Okada, N., & Fujita, T. (2001). Modulation of intestinal permeability by nitric oxide donors: implications in intestinal delivery of poorly absorbable drugs. The Journal of Pharmacology and Experimental Therapeutics, 296(1), 84-90.
Yamamoto A, et al. Modulation of Intestinal Permeability By Nitric Oxide Donors: Implications in Intestinal Delivery of Poorly Absorbable Drugs. J Pharmacol Exp Ther. 2001;296(1):84-90. PubMed PMID: 11123366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of intestinal permeability by nitric oxide donors: implications in intestinal delivery of poorly absorbable drugs. AU - Yamamoto,A, AU - Tatsumi,H, AU - Maruyama,M, AU - Uchiyama,T, AU - Okada,N, AU - Fujita,T, PY - 2000/12/21/pubmed PY - 2001/3/3/medline PY - 2000/12/21/entrez SP - 84 EP - 90 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 296 IS - 1 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 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11123366/Modulation_of_intestinal_permeability_by_nitric_oxide_donors:_implications_in_intestinal_delivery_of_poorly_absorbable_drugs_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11123366 DB - PRIME DP - Unbound Medicine ER -