Isosorbide dinitrate metabolism

Isosorbide is rapidly absorbed and undergoes rapid first-pass metaboHsm by the Hver. The bioavaUabUity of the subHngual and chewable tablets is 59% and 22%, respectively, for the regular tablet. Isosorbide is metabolized to isosorbide-2-mononitrate and isosorbide-5-mononitrate, both of which have pharmacologic activity. The elimination half-Hves of subHngual and po isosorbide dinitrate ate 1 and 4 h, respectively. Those of the 2- and 5-mononitrate metaboHtes are 1.5—3.1 h and 4—5.6 h, respectively. The two metaboHtes prolong the elimination half-life of the dinitrate. Adverse effects with isosorbide are similar to those described for nitroglycerin (99). 

Interestingly, isosorbide dinitrate is also metabolized in the skin when administered for transdermal delivery. During in vitro investigations with porcine skin, ca. 14% of the amount permeated was recovered as IS-2-MN and 10% as IS-5-MN [18]. Because isosorbide was not reported, the relative importance of 2- and 5-denitration cannot be deduced. 

J. E. Riviere, J. D. Brooks, P. L. Williams, E. McGown, M. L. Francoeur, Cutaneous Metabolism of Isosorbide Dinitrate after Transdermal Administration in Isolated Perfused Porcine Skin , Int. J. Pharm. 1996, 127, 213-217. 

After oral administration hepatic first pass metabolism is less than isosorbide dinitrate, hence, systemic bioavailability is more. 

Isosorbide dinitrate [eye soe SOR bide] is an orally active nitrate (Figure 18.3). The drug is not readily metabolized by the liver or smooth muscle and has a lower potency than nitroglycerin in relaxing vascular smooth muscle. 

Orally administered isosorbide dinitrate shows clear hemodynamic and anti-anginal effects, but it undergoes a rapid hepatic first-pass metabolism, with a plasma half-life of ca. 40 min. Its major metabolites are isosorbide-2-mononitrate and isosorbide-5-mononitrate, with half-lives of 2 and 4 h, respectively [16]. A transdermal spray of isosorbide dinitrate can be administered in order to avoid the first-pass effect, and the unchanged drug penetrates through the skin within 20 min so that it is slowly released into the capillaries in therapeutically effective amounts [24]. A very recent study showed intravenously infused isosorbide dinitrate to be ideal anti-anginal agent, especially in acute conditions [25]. 

It is obvious that drugs such as nifedipine and both isosorbide-5-mononitrate and isosorbide dinitrate, which have non-specific, wide absorption sites and so are well absorbed along the entire GI tract, may not be suitable candidates for GRDDS. Also, drugs that are irritant to the gastric mucosa " and those undergoing significant first-pass metabolism may have some limitations. Relevant examples of the latter type are nifedipine, propranolol, levodopa, diltiazem, metopro-lol and 5-fluorouracil. 

The authors concluded that she may have been at increased risk of methemoglobinemia as a result of the metabolic acidosis associated with renal insufficiency, since impaired protein binding of prilocaine could have increased the concentrations of ionized prilocaine. Furthermore, the patient was also taking isosorbide dinitrate, which may have predisposed her to methemoglobinemia. 

Pieper GM, Gross GJ. Salutary action of nicorandil, a new antianginal drug, on myocardial metabolism during ischemia and on postischemic function in a canine preparation of brief, repetitive coronary artery occlusions comparison with isosorbide dinitrate. Circulation 1987 76(4) 916-28. 

GSH conjugation involving substitution at heteroatoms. such as oxygen, is seen often with organic nitrates. For example. nitroglycerin (Nitro.slat) and isosorbide dinitrate (Isordil) ate metabolized by a pathway involving an initial... 

Russek has found isosorbide dinitrate and pentaerythritol tetranitrate to produce a significant improvement in exercise tolerance as well as exercise ECG tests.A wide variety of nitrate esters have been found to provide relief of angina pectoris. There is no information, however, to suggest a difference in the basic pharmacological action of these compounds. Such differences are presumably due to differences in absorption and rates of metabolism. 

Sublingual administration produces maximal plasma concentrations of the drug by 6 minutes, and the fall in concentration is rapid (ty2 of -45 minutes). The major route of metabolism of isosorbide dinitrate in humans appears to be by enzymatic denitration followed by glucuronide conjugation. The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have longer half-lives (3-6 hours) and presumably contribute to therapeutic ejficacy. 

This agent is available in tablet form. It does not undergo significant first-pass metabolism and so has excellent bioavailability after oral administration. The mononitrate has a significantly longer tj 2 isosorbide dinitrate and has been formulated as a plain tablet and as a... 

Riviere, J.E., Brooks, J.D., Williams, R.L., McGowan, E., and Francoeur, M.L., 1996, Cutaneous metabolism of isosorbide dinitrate after transdermal administration in isolated perfused porcine skin, Int. J. Pharm., 127 213—217. 

Dinitrate poorly absorbed and metabolized in the liver to its active metabolite isosorbide mononitrate. Mononitrate well absorbed after PO administration. Excreted in urine and feces. Half-life Dinitrate, 1-4 hr mononitrate, 4 hr. 

Isosorbide mononitrate (Elantan) (t) 4 h) is used for prophylaxis of angina (tabs to swallow). Hepatic first-pass metabolism is much less than for the dinitrate so that systemic bioavailability is more reliable. 

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