In Vitro Metabolism of (Nitrooxy)butyl Ester Nitric Oxide-Releasing Compounds: Comparison with Glyceryl Trinitrate
We investigated the in vitro metabolism of two (nitrooxy)butyl ester nitric oxide (NO) donor derivatives of flurbiprofen and ferulic acid, [1,1â²-biphenyl]-4-acetic acid-2-fluoro-α-methyl-4-(nitrooxy)butyl ester (HCT 1026) and 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-(nitrooxy)butyl ester...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 317; no. 2; pp. 752 - 761 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.05.2006
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Subjects | |
Online Access | Get full text |
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Summary: | We investigated the in vitro metabolism of two (nitrooxy)butyl ester nitric oxide (NO) donor derivatives of flurbiprofen and
ferulic acid, [1,1â²-biphenyl]-4-acetic acid-2-fluoro-α-methyl-4-(nitrooxy)butyl ester (HCT 1026) and 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic
acid 4-(nitrooxy)butyl ester (NCX 2057), respectively, in rat blood plasma and liver subcellular fractions compared with (nitrooxy)butyl
alcohol (NOBA) and glyceryl trinitrate (GTN). HCT 1026 and NCX 2057 undergo rapid ubiquitous carboxyl ester hydrolysis to
their respective parent compounds and NOBA. The nitrate moiety of this latter is subsequently metabolized to inorganic nitrogen
oxides (NOx), predominantly in liver cytosol by glutathione S -transferase (GST) and to a lesser extent in liver mitochondria. If, however, in liver cytosol, the carboxyl ester hydrolysis
is prevented by an esterase inhibitor, the metabolism at the nitrate moiety level does not occur. In blood plasma, HCT 1026
and NCX 2057 are not metabolized to NOx, whereas a slow but sustained NO generation in deoxygenated whole blood as detected
by electron paramagnetic resonance indicates the involvement of erythrocytes in the bioactivation of these compounds. Differently
from NOBA, GTN is also metabolized in blood plasma and more quickly metabolized by different GST isoforms in liver cytosol.
The cytosolic GST-mediated denitration of these organic nitrates in liver limits their interaction with other intracellular
compartments to possible generation of NO and/or their subsequent availability and bioactivation in the systemic circulation
and extrahepatic tissues. We show the possibility of modulating the activity of hepatic cytosolic enzymes involved in the
metabolism of (nitrooxy)butyl ester compounds, thus increasing the therapeutic potential of this class of compounds. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.105.097469 |