Carboxamide excretion

Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation by liver microsomal enzymes by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to 5-aminoimidazole-4-carboxamide, which is excreted in the urine, and diazomethane. The diazomethane generates a methyl carbonium ion that is believed to be the likely cytotoxic species. Dacarbazine is administered parenterally and is not schedule-dependent. It produces marked nausea, vomiting, and myelosuppression. Its major applications are in melanoma, Hodgkin s disease, and soft tissue sarcomas. 

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. 

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. 

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. 

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). 

M3. McGeer, E. G., McGeer, P. L., Miller, J. R., Deny, D., and Nichol, C., Excretion of 5-aminoimidazole-4-carboxamide and creatine creatinine ratios in human and mouse muscular dystrophy. Can. J. Biochem. Physiol. 40, 13 (1962). 

Excess niacin is excreted mainly as the N-methylnico-tinamide (NMN), after methylation in the liver, and the two oxidation products of NMN, N-methyl-2-pyridone-5-carboxamide, and N-methyl-4-pyridone-carboxamide. ... 

At present, no blood markers are commonly used as indicators of niacin status. Most assessments of niacin nutriture have been based on measurement of the 2 urinary metabolites, N -methylnicotinamide and N -methyl-2-pyridone-5-carboxamide. Normally, adults excrete 20% to 30% of their niacin in the form of methylnicotinamide and 40% to 60% as the pyridone. An excretion ratio of pyridone to methylnicotinamide of 1.3 to 4.0 is thus normal, but latent niacin deficiency is indicated by a value below 1.0. As depletion occurs, the pyridone is absent for weeks before clinical signs are noted, and the methylnicotinamide excretion falls to a minimum at about the time that clinical signs are evident.f HPLC methods are currently the methods of choice, though some capillary electrophoresis methods have been developed. However, the measurement of 2-pyridone and N -methylnicotinamide concentrations in plasma may provide a more reliable metabolite ratio than urine measurements. A newer approach that may prove valuable is the ratio of NAD/NADP in erythrocytes and plasma tryptophan. A ratio of NAD/NADP below 1.0 would be indicative of a risk of developing niacin deficiency. ... 

Mathur, B. P., Sensitivity of folic acid. Indian. J. Med. Sci. 20, 133-134 (1966). Newcombe, D. S., The urinary excretion of aminoimidazole-carboxamide in the Lesch-Nyhan syndrome. Pediatrics 46, 508-512 (1970). 

The volume of distribution for ribavirin is large (-10 Ukg) owing to its cellular uptake. Plasma protein binding is negligible. The plasma t, increases to 200-300 hours at steady state, partly because erythrocytes concentrate ribavirin triphosphate and then release it with a of -40 days. Hepatic metabolism and rerml excretion of ribavirin and its metabolites are the principal routes of elimination. Hepatic metabolism involves deribosylation and hydrolysis to a triazole carboxamide. Ribavirin should be used cautiously in patients with creatinine clearances of <50 mUmin. 

V2. Vivian, V. M., Chaloupka, M. M., and Reynolds, M. S., Some aspects of tryptophan metabolism in human subjects. I. Nitrogen balances, blood pyridine nucleotides and urinary excretion of N-methyliiicotinamide and N-methyl-2-pyridone-5-carboxamide on a low-niacin diet. J. Nutr, 66, 587-598 (1958). 

The availability of Mg +, K+, and the folate coenzymes may also be considered. The two cations are probably not rate-limiting, although K+ concentrations do fluctuate in cells. Little is known about the concentrations of total folic acid or of individual folate coenzymes, relative to tissue requirements for them. That this cofactor may be in excess was suggested by a recent study (39) in which a 95% decrease in total H4-folate was induced without causing any change in growth rate of the cells concerned. Others have found, however, that dietary deficiency of folate or vitamin Bi2 leads to increased urinary excretion of aminoimidazole carboxamide (40, 4D-... 

Shibata, K., and Matsuo, H., 1989. Correlation between niacin equivalent intake and urinary excretion of its metabolites, N -methylnicotinamide, N -methyl-2-pyridone-5-carboxamide, and N -methyl-4-pyridone-3-carbox-amide, in humans consuming a self-selected food. The American Journal of Clinical Nutrition. 50 114-119. 

Patients given 5-(3,3-dimethyl-1-triazeno)imidazole-4-carbox-amide (DIC) excrete large amounts of AIC " and DIC is N-demethylat-ed by rat liver microsome to formate and AIC. These facts coupled with the previous observations that 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MIC) decomposes to AIC in aqueous media and shows the same order of activity against leukemia L1210 as DIC, indicate that N-demethylation of DIC to MIC could be essential to its activity. DIC is an effective agent for the treatment of metastatic melanoma and certain... 

Nicotinic acid amide (I), in the form of nicotinamide adenine dinucleotide (NAD+, cf. 2.3.1.1), or its phosphorylated form (NADP+), is a coenzyme of dehydrogenases. Its excretion in urine is essentially in the form of N -methylnicotinamide (trigonelline amide, II), N -methyl-6-pyridone-3-carboxamide (III) and N -methyl-4-pyridone-3-carboxamide (IV) ... 

Under normal conditions there is little or no urinary excretion of either nicotinamide or nicotinic acid. This is because both vitamers are actively resorbed from the glomerular filtrate. It is only when the concentration is so high that the resorption mechanism is saturated that there is any significant excretion. The main urinary metabolites of niacin are Nhmethyl nicotinamide and onward metabolic products, methyl pyridone-2-carboxamide and methyl pyridone-4-carboxamide. 

In addition to the accumulation of 5-methyl THF in the sera of patients with vitamin B12 deficiency (Herbert and Zalusky, 1962), an increase is seen in the excretion of formiminoglutamic acid (Silverman and Pitney, 1958 Rabinowitz and Tabor, 1958), formate (Friedman, 1954 Stokstad, 1966) and carboxamide (McGeer, 1965). 

At present, niacin status is most commonly assessed by the assay of some of the breakdown products of niacin coenzymes in the urine. Of these, -methyl nicotinamide (NMN) is the easiest to measure, because of a convenient conversion in vitro to a fluorescent product, which can then be quantitated without the need for separation. However, more definitive and reliable information can be obtained by the measurement of urinary NMN in conjunction with one or more of the urinary pyridone turnover products (N -methyl-2-pyridone-5-carboxamide and N -methyl-4-pyridone-3-carboxamide), which can be detected and quantitated by UV absorption following high-pressure liquid chromatography. The Interdepartmental Committee on Nutrition for National Defense (USA) selected the criterion of niacin deficiency in humans as an NMN excretion rate of <5.8 tmol (0.8 mg) NMN per day in 24h urine samples. 

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