Modulation of intestinal permeability by nitric oxide donors: implications in intestinal delivery of poorly absorbable drugs.
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.
Yamamoto
A
A
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto, Japan. yamamoto@mb.kyoto-phu.ac.jp
Tatsumi
H
H
Maruyama
M
M
Uchiyama
T
T
Okada
N
N
Fujita
T
T
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000648:ultrastructure; D004553:Electric Conductivity; D004594:Electrophysiology; D005452:Fluoresceins / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology / Q000648:ultrastructure; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014226:Triazenes / Q000494:pharmacology
C114535:1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene; D005452:Fluoresceins; C118603:NOC 12; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D014226:Triazenes; D007770:L-Lactate Dehydrogenase