Glyceryl dinitrate

Lau, D. T. W., Benet, L. Z., Nitroglycerin metabolism in subcellular fractions of rabbit liver. Dose dependency of glyceryl dinitrate formation and possible involvement of multiple isoenzymes of glutathione S-transferases. Drug Metab. Dispos. 18 (1990), p. 292-297... 

D. T. W. Lau, L. Z. Benet, Nitroglycerin Metabolism in Subcellular Fractions of Rabbit Liver. Dose Dependency of Glyceryl Dinitrate Formation and Possible Involvement of Multiple Isozymes of Glutathione S-Transferases , Drug Metab. Dispos. 1990, 18, 292 - 297. 

After 2- days of repeated NG exposure, tolerance to the vasodilatory activity occurs, probably as a result of compensatory vasoconstriction. Tolerance may be lost during periods without NG exposure, such as weekends and holidays. Recent smdies have suggested that tolerance may be mediated by a mitochondrial aldehyde dehydrogenase that catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from NG, leading to production of cGMP and relaxation of vascular smooth muscle. ... 

FIGURE 1.6 In order to avoid extensive hepatic first-pass metabolism, nitroglycerin is given sublingually. GDN = 1,2- or 1.3-glyceryl dinitrate V.C. = vena cava. 

The enzymatic mechanisms of nitrate bioactivation have long been the subject of debate. The glutathione-S-transferase and cytochrome P-450 systems were thought to be involved [8], while recently a nitrate reductase that specifically catalyzes the formation of 1,2-glyceryl dinitrate from glyceryl trinitrate was purified and identified as a mitochondrial aldehyde dehydrogenase [46]. Interestingly, this... 

The organic nitrates are denitrated in the liver after oral administration. Glyceryl dinitrate and isosorbide mononitrate are active metabolites. The latter agent is available as a separate drug. The answer is (C). 

Theoretically speaking, nitroglycerin can mix with nitric acid ester, ethylene glycol dinitrate, diethylene glycol dinitrate, glyceryl dinitrate, glycerol trinitrate isobutyl nitro, azido nitrate, nitric acid hydroxyl ester at any ratio, respectively. The chemical equation of nitroglycerine can be described as follows ... 

Glyceryl trinitrate was converted by rabbits to the mono-and 1,3-dinitrate derivatives, which were excreted in the urine. The isomeric 1,2-glyceryl dinitrate was not detected as a metabolite of glyceryl trinitrate. After the administration of 1,2-glyceryl dinitrate, only glyceryl mononitrate (isomeric position unknown) was detected. The metabolism of penta-erythritol trinitrate (IV), an active metabolite of pentaerythritol tetra-nitrate, was studied in dogs. The major metabolites in the urine were pentaerythritol mononitrate and pentaerythritol only the latter compound was present in the feces. An oral dose of pentaerythritol was excreted unchanged by the dog. ... 

The oldest class of clinically used NO donors are the organic nitrates (R-ONO2) (Fig. 20.3), which are nitric acid esters of mono and polyhydric alcohols, including glyceryl trinitrate (GTN A.l), pentaerithrityl tetranitrate (PETN A.2), isosorbide dinitrate (ISDN A.3), and isosorbide-5-mononitrate (ISMN A.4). Metabolites of GTN, viz., glyceryl mononitrate (GMN) and glyceryl dinitrate (GDN), are pharmacologically active, but less potent than GTN. 

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