Methyluric acid

The key metabolites of caffeine (a trimethylxanthine) found in plasma, are the dimethylxanthines paraxanthine, theophylline, and theobromine the monomethylxanthine 1-methylxanthine the C-8 oxidized monomethylxanthine 1-methyluric acid and the ring oxidized uracil 5-acetyl-amino-6-amino-3-methyluracil. 

MefaboZ/sm/Excref/on-Xanthines are biotransformed in the liver (85% to 90%) to 1, 3-dimethyluric acid, 3-methylxanthine and 1-methyluric acid 3-methylxanthine accumulates in concentrations approximately 25% of those of theophylline. 

Antioxidant activities of caffeine (1,3,7-trimethylxanthine) and its main metabolites was compared. Caffeine, 1,7-dimethylxanthine, and 3,7-dimethylxanthine did not show any peroxyl radical-scavenging capacity at concentration up to 100 fxM. Flowever, the relative antioxidant activities (with respect to Trolox) of 1-methyl-xanthine and 1-methyluric acid were 0.82 and 0.58, respectively (L9). 

Disposition in the Body. Rapidly absorbed after oral administration bioavailability almost 100%. Metabolic reactions include V-demethylation and oxidation to uric acid derivatives. About 85% of a dose is excreted in the urine in 48 hours with up to 40% of the dose as 1-methyluric acid, 10 to 15% as 1-methylxanthine and up to 35% as 5-acetylamino-6-formylamino-3-methyluracil and 5-acetylamino-6-amino-3-methyluracil other metabolites excreted in the urine include theophylline, 1,7-dimethylxanthine (paraxanthine), 7-methylxanthine, and 1,3-dimethyluric acid. Less than 10% is excreted in the urine as unchanged drug. The extent of V-acetylation is genetically determined. Caffeine, theophylline, theobromine, and paraxanthine are found in plasma from dietary sources especially coffee, tea and cocoa. An average cup of coffee or tea contains approximately 100 mg of caffeine. 

Disposition in the Body. Readily absorbed after oral administration of aminophylline less rapidly absorbed when given as theophylline irregularly absorbed after rectal administration. Rapidly and widely distributed throughout the tissues. Metabolised by V-demethylation to form 3-methylxanthine (which is active but less potent than theophylline), 1,3-dimethyluric acid, and 1-methyluric acid. In adults, about 13% of a dose is excreted in the urine in 24 hours as unchanged drug, with about 15% as... 

Alkylation of the triethylsilylated uric acid (120) with methyl iodide is unusual in produdng 1-methyluric acid but at 150 °C with dimethyl sulfate the major products isolated were... 

Caffeine is rapidly absorbed after an oral dose, with peak levels reached within 1-2 h at therapeutic doses. Onset of clinical effects occurs within 60 min. In adults, caffeine is extensively metabolized by the liver primarily by N-demethylation. It is excreted in the urine primarily as 1-methyluric acid and 1-methylxan-thine. Theophylline (1,3-dimethylxanthine) is a minor product of caffeine metabolism in adults (< 1%). After massive caffeine overdoses, serum levels of theophylline are measurable. The elimination half-life of caffeine is 3-6 h at therapeutic doses. The half-life is shorter in smokers and is prolonged by oral contraceptives, cimetidine, late pregnancy, and in overdose. The half-life of caffeine is much longer in infants and does not approximate that seen in adults until 6 months of age. The half-life of caffeine may exceed 100 h in preterm infants. Only 1-10% of caffeine appears unchanged in the urine in adults. Neonates may excrete up to 85% of caffeine unchanged. 

Fig. 11.1. Separation of some xanthine derivatives Column pBondapak C18 (300x4 rim ID), mobile phase acetonitrile - 0.01 M sodium acetate buffer (pH 4.0) (7 93), flow rate 2.0 ml/min, detection UV 254 nm. Peaks 1, 1-methyluric acid 2, 3-methyl xanthine 3, 1,3-dimethyl-uric acid 4, theobromine 5, theophylline 6, B-hydroxy-ethyltheophylline 7, phenobarbital 8, caffeine 9, 8--chlorotheophyl1ine. (reproduced with permission from ref. 56, by the courtesy of Clinical Chemistry)...

Precolumn Lichrosorb RP2 10 pm (40x2.1 mm ID), column Ultrasphere ODS 5 pm (250x4.6 mm ID), mobile phase gradient with solvent A 0.01 M sodium acetate and 0.005 M tetrabutylammonium hydrogen sulfate in water (pH 4.9), solvent B same salt concentrations in 50% methanol (pH 4.8). Gradient 0-7.5 min 0 B, 7.5-15 min 0-T5% B, 15-25 min 15-30% B, 25-33 min 30-32% B, 33-38 min 32-45% B and 38-41 min 45-0% 6. Detection UV 280 nm. Peaks 1, xanthine 2, uric acid 3, 3-methyluric acid 4, 7-methyl xanthine 5, 3-methyl xanthine 6, 1-methylxanthine 7, theobromine 8, 3,7-dimethyl uric acid 9, 7-methyluric acid 10, 1-methyluric acid 11, 1,3-dimethyluric acid 12, 1,7-dimethyl xanthine 13, theophylline 14, e-hydroxyethyltheophylline (internal standard) 15, 1,7-dimethyluric acid 16, 1,3,7-trimethyluric acid 17, caffeine, (reproduced with permission from ref. 192, by the courtesy of Journal Chromatographic Science)... 

The urinary ratio of 1-methyluric acid to 1-methyl-xanthine after a caffeine challenge can be used as a means to assess XO activity in vivo. 

Noninterfering 1,3-dimethyluric acid, hypoxanthine, 1-methyluric acid, 1-methylxan-thine, 3-methylxanthine, 7-methylxanthine, theobromine... 

Although scarcely detectable in adults, the conversion of theophylline to caffeine is significant in preterm infants. In this setting, caffeine accumulates in plasma to a concentration —25% that of theophylline. About 50% of the theophylline administered to such infants appears in the urine unchanged the excretion of 1,3-dimethyluric acid, 1-methyluric acid, and caffeine derived from theophylline accounts for nearly all the remainder. 

Hepatic metabolism is predominantly mediated via the cytochrome P-450 (CYP) isoenzymes CYP2E1 and CYP3A4 (8-hydroxylation to 1,3-dimethyluric acid, 40 to 50%), and CYP1A2 (A-demethylation to 3-methylxanthine, 10 to 15%, and 1-methylxanthine). 1-Methylxanthine is further oxidized, by xanthine oxidase, to 1-methyluric acid (15 to 20%). " Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacological activity, but only... 

Oral coadministration of 5 ml/kg of a cayenne suspension (10% cayenne) and 20 mg/kg theophylline to rabbits significantly increased the plasma levels of theophylline (Bouraoui et al. 1988), whereas oral administration of cayenne (5 ml/kg of a 10% cayenne suspension) and intravenous administration of theophylline (12 mg/kg) did not affect the plasma levels of theophylline (Bouraoui et al. 1995). Dosing with cayenne and theophylline for 7 days in rabbits significantly reduced urinary excretion of the theophylline metabolite 1-methyluric acid (Bouraoui et al. 1995). 

Theophylline and four of its liver metabolites (1-methyluric acid, 1,3-dimethy-luric acid, 3-methylxanthine, uric acid) were extracted from tissue and baseline resolved on a C,g column (/ = 273nm) using a 13/87 methanol/water (5mM tetrabutylanunonium hydrogensuliate with lOtnM sodium acetate at pH 4.75) mobile phase [588]. Peak shapes were excellent and elution was complete in 20 min. 

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