Paraxanthine

Paraxanthine—see Xanthine, 1,7-dimethyl-Parent name nomenclature, 1, 35 Parham cycloalkylation in chroman synthesis, 3, 783 Paromomycins as pharmaceuticals, 1, 154 Partial charge transfer from donor to acceptor stacks, 1, 350 Pasteurellosis... 

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. 

N-demethylation at the three N-methyl sites. In this regard, the 3-N-demethylation of caffeine to generate paraxanthine can serve as a particularly good in vivo indicator of the presence and activity of CYP1A2 (Fig. 4.7). In the case of phenacetin, CYP1A2 catalyzes N-deethylation to generate acetaminophen. Not unexpectedly, 1 A2 s selectivity toward heterocyclic aromatic substrates carries over to inhibitors of the enzyme. Furafylline (Fig. 4.7) is an example of a particularly potent 1A2 mechanism-based inhibitor. 

Caffeine pharmacokinetics are nonlinear. For example, when comparing a 500 mg dose to a 250 mg dose, the clearance is reduced and elimination half-life is prolonged with the higher dose (Kaplan et al. 1997). Thus, larger doses prolong the action of the drug. Active metabolites of caffeine are paraxanthine, and to a lesser degree, theobromine, and theophylline. Urinary metabolites are I-methylxanthine, l-methyluric acid, and an acetylated uracil derivative. 

Wilkinson JM, Pollard I. (1993). Accumulation of theophylline, theobromine, and paraxanthine in the fetal rat brain following a single oral dose of caffeine. Brain Res Dev Brain Res. 75(2) 193-99. Winstock AR, Trivedy CR, Warnakulasuriya KAAS, Peters TJ. (In press). A dependency syndrome related to areca nut use some medical and psychological aspects among areca nut users in the Gujarat community in the UK. Addict Biol. 

Walton et al. (2001a) examined data for compounds eliminated by the cytochrome P450 isoenzymes CYP1A2 in humans. Absorption, bioavailabihty, and route of excretion were generally similar between humans and the test species for each of the substances (caffeine, paraxanthine, theobromine, and theophylline). However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceeded the fourfold default factor for toxicokinetics, whereas the rabbit (2.6) and the dog (1.6) were below this value. 

Many antibiotics produced by various microorganisms are nucleosides (2). Among these are nebularine, cordycepin, and nucleocidin. The only known purines in higher plants shown to be involved In allelopathy are caffeine, theophylline, paraxanthine, and theobromine from the coffee tree... 

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. 

One study carried out between 1959 and 1966 found that very high levels of a caffeine metabolite is a marker for spontaneous abortion. Measured at 11 weeks gestation, the amount of the metabolite, paraxanthine, in blood semm was higher in women who had lost a pregnancy than in women in the control group. The risk of spontaneous abortion in women with the very highest level of paraxanthine was twice that than for the women with the lowest recorded levels. The levels were measured more than 30 years later, and the findings reported in 2000. 

The relative safety of caffeine has lead to its widespread use as an in vivo probe for CYP1A2 activity in man. The primary route of caffeine metabolism is via N-demethylation to paraxanthine, theophylline, and theobromine. The major route of caffeine clearance in man is to paraxanthine (57). The N-3-demethylation of caffeine to paraxanthine has been shown to be mediated by CYP1A2 (58). However, paraxanthine is further metabolized to a number of different products, and as a consequence urinary metabolic ratios are often used to describe an individual CYP1A2 phenotype. 

In an attempt to further simplify the caffeine phenotyping test, a trait measure based on the plasma or salivary paraxanthine caffeine concentration ratio between three hours and seven hours after administration of the probe has been suggested (56). High linear correlations (>0.89) have been observed between this trait value and caffeine s oral clearance, and if necessary, a predicted caffeine clearance value may be calculated from the ratio (56). Currently, this phenotyping approach appears to be the simplest and most noninvasive means of readily assessing CYP1A2 activity using caffeine as a probe in addition, the method is reproducible and appears to be robust (56), despite the theoretical dependency of the trait value on the urine flow rate (51). 

Fuhr U, Rost KL. Simple and reliable CYP1A2 phenotyping by the paraxanthine/ caffeine ratio in plasma and in saliva. Pharmacogenetics 1994 4 109-116. 

The PA caffeine is produced from xanthosine via three distinct N-methylations (Fig.7.5).87 89 Partially purified enzyme extracts from tea (Camellia senensis) and coffee (Coffea arabica) were shown to exhibit all three activities, suggesting either that the A-methyltransferase steps in caffeine biosynthesis are catalyzed by a single enzyme, or by multiple enzymes with similar properties.90 However, a specific A-methyltransferase purified from coffee was active only toward 7-methylxanthine and theobromine91 An A-methyltransferase catalyzing the methylation of methylxanthines and designated caffeine synthase (CS) was purified from tea.92 CS catalyzes two consecutive methylations involved in the conversion of 7-methylxanthine to caffeine, but is inactive toward xanthosine, indicating that the first methylation proceeds via a different enzyme. Heterologous expression of the CS cDNA showed that the enzyme was active toward 7-methylxanthine, paraxanthine,... 

On Days 1 and 10 CYP 1A2 activity was monitored using the plasma concentrations of caffeine and paraxanthine and CYP 3A4 activity was monitored using the urinary excretion of free cortisol and 6-(3>-hydroxy-cortisol. 

Plasma concentrations of Drug XYZ, caffeine and paraxanthine, before and at pre-determined times post dose were measured. 

Plasma caffeine and paraxanthine Descriptive pharmacokinetic parameters (standard parameters including peak concentrations (Cmax), time of Cmax (Tmax), area-under-the-curve (AUC) between time 0 and time t where t = 24 h post dose (AUCo-t), AUC after extrapolation to infinity (AUCo-co), apparent terminal half-life total clearance (CL)) for... 

Table 13 Mean (SD) plasma caffeine and paraxanthine pharmacokinetic variables (ng.h/mL) by treatment.

The mean AUCo-oo for caffeine on Day 10 was decreased by approx. 67 %, and approx. 80 % when compared to Day 1 for subjects treated with 400 mg and 1200 mg Drug XYZ, respectively, and was more pronounced than for caffeine and paraxanthine mean AUCo-t values, which also decreased substantially... 

Administration with placebo showed no notable change in caffeine or paraxanthine levels... 

All the caffeine / paraxanthine results suggest that Drug XYZ induced CYP 1A2 in humans and that the extent of induction was dependent on the dose administered... 

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... 

The adjustment of die pH is critical for the separation of 8-chlorodieophylline. UV detection is at 280 nm. Other xandiines and xandiine metabolites also elute from this system. Retention times relative to theophylline are 3-methylxanthine, 0.49 theobromine, 0.63 paraxanthine, 0.88 caffeine, 1.36 ... 

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. 

Isopropyl alcohol 2-Propanol Paraxanthine 17f-Purine-2,6-dione, 3,7-dihydro-1,7-dimethyl-... 

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 completely absorbed within the intestine, and about 97% is metabolized selectively by the liver - relatively independently of perfusion - by way of microsomal demethylation (E. Renner et af, 1984). After intravenous administration of 125 mg caffeine (with 125 mg sodium benzoicum) - equivalent to 1 cups of coffee -a plasma caffeine increase was detected in liver patients, corresponding to the limited demethylation capacity via paraxanthin. The prolongation of half-life and the limitation of plasma clearance (PC) were clearly altered in patients suffering from cirrhosis. The result can be influenced by age, smoking, contraceptives and numerous medicaments, etc. The test shows no side effects, it is cost-favourable and easy to carry out. (56, 70, 73,81,87)... 

Whether the consumption of caffeine dnring pregnancy increases the risk of spontaneons abortion is controversial. In a nested case-control stndy, 591 women who had a spontaneous abortion before 140 days of gestation were compared with 2558 matched women from the same clinic who gave birth to live infants at 28 weeks gestation and who had serum drawn on the same day of gestation as the women who had abortions (35). The women were enrolled in the Collaborative Perinatal Project from 1959 to 1966, and the serum paraxanthine concentration was measured 30 years later. Moderate consumption of caffeine was unlikely to increase the risk of spontaneous abortion only extremely high serum paraxanthine concentrations were associated with spontaneous abortion. 

Klebanoff MA, Levine Rl, DerSimonian R, Clemens JD, Wilkins DG. Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion. N Engl J Med 1999 341(22) 1639-44. 

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