Inorganic nitrite was produced by cultured smooth muscle cells when GTN was added to the culture dish. Nitrite production increased with increasing GTN concentration and with incubation time.
The enzymatic nature of GTN metabolism to nitrite was assessed by enzyme inhibition studies. Indocyanine green, a non-substrate inhibitor of glutathione S-transferase, inhibited GTN metabolism by smooth muscle cells. Cellular glutathione is also involved in GTN metabolism by the smooth muscle cell. Pretreatment with phorone, a glutathione S-transferase substrate, depleted cellular glutathione and decreased nitrite production from GTN.
Pretreatment with buthionine sulfoximine, inhibitor of gamma-glutamylcysteine synthetase, decreased intracellular glutathione and caused decreased GTN metabolism in smooth muscle cells.
Removal of cysteine from the smooth muscle cell incubation medium in combination with buthionine sulfoximine pretreatment decreased GTN metabolism to a lower level than buthionine sulfoximine pretreatment alone.
Therefore, nitroglycerin is totally absorbed by the intestinal mucosa but undergoes a massive hepatic first pass effect , rendering its oral bioavailability negligible. Sublingual, intravenous or transdermal administration of nitroglycerin partially by passes this first pass effect, allowing plasma concentration to reach the therapeutic range.
Nitroglycerin has a large volume of distribution due to its high liposolubility and to tissular protein binding. Nitroglycerin metabolites are excreted through the kidneys.
For the acute treatment of angina, nitroglycerin is available as capsules to be chewed, sublingual tablets and mouth spray. Injection solutions are available for the treatment of conditions such as acute myocardial infarction.
0コメント