1.7-dimethylxanthine

Closely related methylxanthines include theophylline (1,3-dimethylxanthine), theobromine (3,7 dimethylxanthine) and paraxanthine (1,7-dimethylxanthine). Theobromine is found primarily in chocolate. These derivatives of caffeine are important because they are pharmacologically active and also are the common metabolites of caffeine. 

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). 

There are two commonly used and robust methods for phenotyping. The first one measures caffeine (1,3,7-methylxanthine) and its N-demethylated metabolite 1,7-dimethylxanthine (paraxanthine) in a plasma or saliva sample collected within 5 to 7 hours post caffeine dosing (Fuhr and Rost 1996). The second one uses the assay of the metabolites 1-methylurate... 

Theobromine was isolated from the seeds of the cacao tree and then shortly afterward was synthesized from xanthine by Fischer.132 Theobromine is the primary bitter-tasting alkaloid found in cocoa and chocolate chocolate contains 0.5—2.7% theobromine. Theobromine is water insoluble and is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as 3,7-dimethylxanthine while theophylline is 1,3-dimethyl-7f/-purine-2,6-dione and paraxanthine is 1,7-dimethylxanthine. Theophylline is known to be a bitter-tasting principle of green tea. Theobromine is used as a vasodilator (a blood vessel widener), as an aid in urination, and... 

Theobromine and theophylline are metabolites of caffeine in the horse (M. S. Moss, 1977), and theobromine is frequently ingested with caffeine as a result of the contamination of pelleted horse feed with cocoa husk. Theophylline may also occur as a result of administering aminophylline for respiratory problems. Caffeine appears occasionally in greyhound urine as a result of the widespread practice of giving tea prior to racing. Theobromine, theophylline, and 1,7-dimethylxanthine are all metabolites of caffeine in the horse and man but tiieir proportions vary greatly between the species. In human sport, the upper limit on the urinary concentration of caffeine has recently been set at 15 xg/ml. 

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. 

Methylxanthine is the major purine constituent of human urine (3.1 g in 10001) (1898ZPC(24)364). 3- and 7-Methylpurines are also minor constituents of urine, especially following large doses of caffeine or other methylated xanthines. 1,3-Dimethylxanthine (theophylline) occurs with caffeine in tea leaves and is a powerful diuretic and has been used clinically for this purpose (generally as an adduct with salts of organic acids) and also in the treatment of asthma. 1,7-Dimethylxanthine (paraxanthine) is also an efficient diuretic and, in addition, possesses antithyroid properties (45JCS751). The main purine constituent... 

Caffeine is noted for its ability to stimulate the CNS and also has positive inotropic and mild diuretic activity. Theophylline (1,7-Dimethylxanthine) is noted for its smooth muscle relaxant activity and its use for chronic asthma. 

By the addition of tetrahydrofuran to the above mentioned mobile phase and by increasing the pH of the buffer to 5 the interference of 1,7-dimethylxanthine could be obviated106,122. The same was the case with the other drugs mentioned above (ampicillin, etc.). Also, by decreasing the percentage of acetonitrile in the mobile phase, the interference of ampicillin could be eliminated111. With ageing of the columns, Marion et al.176 found that procainamide interfered with theophylline. 

To separate theophylline from 1,7-dimethylxanthine, Rodriguez et al.177 used methanol -formamide - potassium dihydrogen phosphate (0.05 M)(22 11.5 66.6)(pH 5.8) in combination with an octadecyl type of column. 

Boeckx et al. found that the advantage of the assay mentioned, over methods based on reversed-phase separations, was that silica gel columns used in combination with a simple extraction had a longer life than reversed-phase columns used in combination with a direct injection of deproteinized samples. To avoid the interference of 1,7-dimethylxanthine, a caffeine metabolite, in the analysis of theophylline in biological fluids, Van Aerde et al.165 developed a separation on silica gel. As the mobile phase, chloroform - dioxane - formic acid (99.5 4.5 0.01) was used. 

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)...

Methylated xanthines like caffeine are degraded in humans and rats by oxidative removal of methyl groups [10], Thus caffeine goes to 1,7-dimethylxanthine and 1-methylxanthine [11]. After the first demethylation there is an alternate pathway producing 5-acetylamino-6-formylamino-3-methyluracil. This pathway is more active in people with a more active acetylation system [12, 13]. There are individual, quantitative differences in the activity of this pathway in humans. In rats a major metabolite is... 

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

Recent research has begun to characterize the presence of ECs in a variety of waste sources (e.g., wastewater treatment plants, onsite septic systems, etc.) to better understand their potential pathways into the environment. Although data on transformation products for emerging contaminants is more limited when compared to other compounds, such as pesticides, a growing number of methods to detect such transformation products are being developed and select compounds have been found in a variety of waste sources, including wastewater treatment plants [7,67,74-78], septic systems [13,79], landfills [80], and animal manure [81,82]. For example, in a study of waste from wastewater treatment plants [75] and septic systems [13] (Tables 2-3), 1,7-dimethylxanthine (caffeine metabolite), 4-nonylphenol diethoxylate and... 

The first national-scale study of emerging contaminants in the United States found that such compounds were commonly present in stream systems, with 80% of the streams sampled having at least one compound detected [11]. Over 60% of the chemical concentrations exceeding 1 xg/L were from three detergent metabolites (4-nonylphenol, 4-nonylphenol monoethoxylate, and 4-nonylphenol diethoxylate). In addition, transformation products also were frequently detected (e.g., cotinine, 1,7-dimethylxanthine, erythromycin H2O). This study indicated the enormous potential for parent compoimds to degrade during environmental transport and for the transformation products to contribute much of the relative loading of these contaminants. The results confirm the need to include both parent compoimds and transformation products in occurrence studies. 

Caffeine is usually absorbed rapidly, especially in the small intestine, and overcomes the blood/brain barrier without problems. The bioavaUability is greater than 90%. The drug is deactivated in the liver by cytochrome P 450 enzymes. The methyl groups are an essential part of the pharmacophore. After their oxidative removal, caffeine loses its activity. The primary metabolites are theophylline, theobromine and 1,7-dimethylxanthine. 

Coumarin 7-hydroxylation can be used in vivo with humans as a phenotypic assay. An alternative procedure is to administer caffeine to individuals and determine the conversion of 1,7-dimethylxanthine to 1,7-dimethyluric acid, a reaction catalyzed by P450 2A6 [424]. 

Kimura M, Yamazaki H, Fujieda M, Kiyotani K, Honda G, Saruwatari J, Nakagawa K, Ishizaki T, Kamataki T (2005) CYP2A6 is a principal enzyme involved in hydroxylation of 1,7-dimethylxanthine, a main caffeine metabolite, in humans. Drug Metab Dispos 33 1361-1366... 

Although xanthines such as theophylline (Figure 6.61) are electroactive, " the relatively high potentials (for example +1.2 V vs Ag/AgCl) that are required means that ED offers little advantage over UV detection, particularly if the eluent is chosen to ensure resolution of the caffeine metabolite 1,7-dimethylxanthine. 

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