Nicotinamide excretion

Nicotinamide is present in pork, beef, chicken, and fish. 2-Py and 4-Py are the major metabolites of nicotinic acid and nicotinamide excreted in urine. The contents of 2-Py and 4-Py in blood are below the limit of detection (33). The HPLC methods for analysis of nicotinamide and the related compounds are summarized in Table 4. Shibata et al. (34) reported the simultaneous measurement of nicotinamide, 2-Py, and 4-Py. This method is commonly applicable not only to urine and pharmaceutical preparations but also biological materials and foods. Chromatograms of a reference mixture of isonicotinamide (used as an internal standard), nicotinamide, 2-Py, and 4-Py and of extracts of rat urine, human urine, rat liver, and of the extract of multivitamin preparations are shown in Figure 10. The detection limits for nicotinamide, 2-Py, and 4-Py were 4 pmol (552 pg), 10 pmol (1220 pg), and 2 pmol (304 pg), respectively, at a signal-to-noise ratio of 5 1. Daily urinary excretion of nicotinamide, 2-Py and 4-Py in rats, mice, guinea pigs, hamsters and humans is given in Table 5. 

Other reactions of pyridine nucleotides. Alkaline hexacyanoferrate (III) oxidizes NAD+ and NADP+ to 2-,4-, and 6-pyridones. The 6-pyridone of N-methyl-nicotinamide is a well-known excretion product of nicotinic acid in mammals. Reoxidation of NADH and NADPH to NAD+ and NADP+ can be accomplished with hexacyanoferrate (III), quinones, and riboflavin... 

Pharmacokinetics Niacin is administered orally. It is converted in the body to nicotinamide, which is incorporated into the cofactor nicotinamide adenine dinucleotide (NAD+). Niacin, its nicotinamide derivative and other metabolites are excreted in the urine. [Note Nicotinamide alone does not decrease plasma lipid levels.]... 

Under normal conditions, there is litde or no urinary excretion of either nicotinamide or nicotinic acid, because both vitamers are actively reabsorbed from the glomerular filtrate. It is only when the concentration is so high that the transport mechanism is saturated that there is any significant excretion. 

Nicotinamide can also undergo oxidation to nicotinamide A7-oxide. This is normally a minor metabolite in human beings, unless large amounts (about 200 mg) of nicotinamide are ingested, in the mouse, nicotinamide Al-oxide is the major excretory product of niacin metabolism. At high levels of nicotinamide intake, some 6-hydroxynicotinamide may also be excreted. 

A number of studies have investigated the equivalence of dietary tryptophan and preformed niacin as precursors of the nicotinamide nucleotides, generally by determining the excretion of -methyl nicotinamide and methyl pyridone carboxamide in response to test doses of the precursors, in subjects maintained on deficient diets. 

The two methods of assessing niacin nutritional status are measurement of blood nicotinamide nucleotides and the urinary excretion of niacin metabolites, neither of which is wholly satisfactory. 

Urinary Excretion of N -Methyl Nicotinamide and Methyl Pyridone Carboxamide... 

The most widely used method for assessing niacin nutritional status is measurement of the urinary excretion of niacin metabolites. Table 8.1 shows the excretion of A( -methyl nicotinamide and methyl pyridone carboxamide in niacin adequacy and deficiency. 

The depletion/repletion studies of Horwitt et al. (1956) and others have suggested, on the basis of restoration of urinary excretion of -methyl nicotinamide, that the average niacin requirement is 5.5 mg per 1,000 kcal (1.3 mg per MJ). Allowing for individual variation, reference intakes (see Table 8.2) are set at 6.6 mg niacin equivalents (preformed niacin - -1 /60 of the dietary tryptophan) per 1,000 kcal (1.6 mgper MJ). Even when energy intakes are very low, it must be assumed that energy expenditure will not fall below 2,000 kcal, and this is the basis for the calculation of reference intakes for subjects with low energy intakes. 

Disposition in the Body. Readily absorbed after oral administration. Metabolised to A -methylnicotinamide, A-methyl-6-oxo-pyridine-3-carboxamide, iV-methyl-4-oxopyridine-3-carbox-amide, and by glycine conjugation to nicotinuric acid. It is rapidly excreted in the urine, and after administration of therapeutic doses about 34% is excreted unchanged in 6 hours. Nicotinic acid is a metabolite of nicergoline, nicotinamide, and nicotinyl tartrate. 

Disposition in the Body. Rapidly absorbed after oral or parenteral administration and metabolised by V-dealkylation to V-ethyl-nicotinamide and nicotinamide rapidly excreted in the urine the major urinary metabolite is V-ethylnicotinamide. 

The excretion of methyl pyridone carboxamide is more severely reduced in marginal niacin deficiency than is that of -methyl nicotinamide. The excretion of methyl pyridone carboxamide decreases rapidly in subjects fed on a niacin-deficient diet, and virtually ceases several weeks before the appearance of clinical signs of deficiency by contrast, a number of studies have shown continuing excretion of -methyl nicotinamide even in pellagrins. A better estimate of niacin nutritional status can be obtained by determining the ratio of urinary methyl pyridone carboxamide Ai -methyl nicotinamide, which is relatively constant, despite the administration of loading doses of tryptophan or niacin to adequately nourished subjects (between 1.3 to 4.0), and a ratio of less than 1.0 indicates depletion of niacin reserves (de Eange and Joubert, 1964 Dillon et al., 1992). 

Hartnup s disease. There is a defect in the epithelial transport of neutral amino acids (e.g., tryptophan) leading to poor absorption and excess excretion of these amino acids. Clinical signs resemble those of niacin deficiency (tryptophan is a precursor of niacin), namely the 3 D s Diarrhea, Dementia, Dermatitis. The condition responds to nicotinamide administration. Fan-coni s syndrome is a more generalized defect in molecular transport, involving a multitude of amino acids, glucose, calcium, phosphate, proteins, and other molecules. There may be decreased growth and rickets. 

In patients suffering from schizophrenia urinary excretion of both N-methyl-nicotinamide and xanthiurenic acid was determined (L6) after 10 g DL-tryptophan loadings. Excretion of the former was significantly decreased, in comparison with that of normal controls, whereas an increase was found in that of xanthurenic acid. 

For the authors (PIO) the simplest explanation of the data on tryptophan metabolism in these 3 patients would be as follows in scleroderma (acrosclerosis) there was an abnormal urinary excretion of kynurenine and its metabolites after oral ingestion of tryptophan. The administration of pyridoxine or pyridoxine plus nicotinamide partially corrected the metabolic abnormality. The efficacy of pyridoxine plus Na2EDTA could be explained on the basis of a decrease in tissue calcium and zinc (and possibly other cations), enabling the metal ions, normally functioning with pyridoxal phosphate, as magnesium ions, to be utilized more advantageously. 

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