Dimethyluric acids

A novel approach to purine synthesis involves the use of ADC compounds as a source of one nitrogen atom in the five-membered ring.148 150 Treatment of 6-amino-l,3-dimethyluracil (94, R = H) with DEAZD gives the 5-substitution product (95, R = H). The N—N bond is cleaved by Raney nickel or formic acid, and ring closure to 1,3-dimethyluric acid is simply effected by heating.148 Whether the initial adduct is formed by a substitution... 

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. 

Dimethyluric Acid. — The reduction to 1.3-dimethyl-puron takes place very slowly in a 75% sulphuric acid solution. The molecular rearrangement to isopuron is also very slow. 

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... 

Theophylline 7-oxide 1,3-Dimethyluric acid Heat 66LA(691)142... 

The synthetic potential of a simple method for the direct introduction of nitrogen into the 5-position of the pyrimidine ring is illustrated by the synthesis of 1,3-dimethyluric acid (15) from 1,3-dimethyluracil-6-amine by reaction with diethyl azodicarboxylate, reduction to 5-[(ethoxycarbonyl)amino]-l,3-dimethyluracil-6-amine, and thermal ring closure. "... 

Serum of uraemic patients must not be examined in the Seralyzer, since the metabolite of 1,3-dimethyluric acid simulates a high theophylline concentration (SI 16, SI32, SI38). In a normal patient the 1,3-dimethyluric acid con-... 

Fig. 11.2. Separation of some xanthine derivatives and urinary metabolites Column uBondapak C18 (300x4 mm ID), mobile phase acetonitrile - 0.1 M disodium hydrogen phosphate and 0.1 M sodium dihydrogen phosphate in water (2 38), flow rate 1.5 ml/min, detection UV 254 nm. Peaks 1, uric acid 2, creatinine 3, 1-methyluric acid, 3-methyluric acid and 7-methyluric acid 4, xanthine 5, 7-methylxanthine 6, 1,3-dimethyluric acid 7, 3-methyl-xanthine 8, 1-methylxanthine 9, theobromine 10, 8-chlorotheophyl1ine 11, theophylline and 1,7-dimethylxanthine (paraxanthine) 12, dyphylline 13, caffeine, (reproduced with permission from ref. 80, by 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)... 

Experiments with liver slices and cultured cell lines have corroborated this pathway of purine degradation. In human liver slices 16 xanthine derivatives were produced from caffeine by action of P-450 system. Demethylation at N-3 was the most prominent process [18, 19]. Comparison of cell lines from humans, hamsters, mice, and rats show some interspecies differences but all of them demethylated and oxidized caffeine [20]. Human liver cells give 1,3,7-trimethylurate as the major metabolite of caffeine, but also made were the intermediate products theobromine, theophylline, and paraxanthine [21]. Human liver microsomes convert theophylline to 1-methylxanthine, 3-methylxanthine, and 1,3-dimethyluric acid [22, 23]. Human kidney microsomes produced each of the three possible demethylated products as well as 1,3,7-... 

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... 

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