Caffeine metabolites

Schneider H, Ma L, Glatt H. 2003. Extractionless method for the determination of urinary caffeine metabolites using high-performance liquid chromatography coupled with tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 789 227. 

Krul C, Hageman G (1998) Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reversed-phase high-performance liquid chromatography, J ChromatogrB Biomed Sci Appl 709(l) 27-34... 

Caffeine (3,7-dihyro-l,3,7-trimethyl-lH-purine-2,6-dione) is a natural product from tea, coffee, and other plants, and is present in many beverages and food. It is primarily metabolized in the liver by cytochrome P450 enzymes to give M-demethylated xanthine and few other metabolites (Fig. 2) [2,48 - 50]. About 17 caffeine metabolites have been identified in humans [51]. 

Kolakowski, B. M., Lustig, D., and Purves, R. W. (2004). Separation and quantitation of caffeine metabolites by high-field asymmetric waveform ion mobility spectrometry (FAIMS). 

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. 

Kalow W, Tang BK. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther 1991 50 508-519. 

Denaro CP, Wilson M, Jacob P El, et al. Validation of urine caffeine metabolite ratios with use of stable isotope-labeled caffeine clearance. Clin Pharmacol Ther... 

Kilbane AJ, Silbart LK, Manis M, et al. Human N-acetylation genotype determination with urinary caffeine metabolites. Clin Pharmacol Ther 1990 47 470-477. 

Han XM, Ou-Yang DS, Lu PX et al. (2001) Plasma caffeine metabolite ratio (17X/137X) in vivo associated with G-2964A and C734A polymorphisms of human CYP1A2. Pharmacogenetics 11 429-435... 

FIGURE 22.6 Paired comparisons of measured ratios of caffeine metabolites to parent drug in nonpregnant (solid bars) and pregnant (open bars) women. Comparisons were made of the metabolic activities of CYP1A2, xantlaine oxidase (XO), W-acetyl transferase (NAX), and CYP3A4 = P <0.05, = P <0.005). (Data from Bologa M... 

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. 

El-Yazigni A, Chaley K., Martin CR. A simplified and rapid test for acetylator phenotyping by use of the peak height ratio of two urinary caffeine metabolites. Clin Chem 1989 35 848-51. 

Figure 43-12 Histogram of NAT2 phenotypical activities as obtained by the caffeine test 5 hr urine collection obtained after administration of caffeine, and analyzed for caffeine metabolite concentrations.Values represent the logarithmically transformed ratio of metabolites 5-acetylamino-6-formylamino-3-methy -uracil (AFMU) and I-methyixanthine (IX). From the distinct biomodal distribution an anti mode of log(0.50)...

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. 

Caffeine has been used to phenotype NAT2 using the urinary ratio of the caffeine metabolite, 5-acetylamino-6-formylamino-3-uracil (AFMU), or 5-acetyl-6-amino-3-uracil (AAMU), to various other caffeine metabolites (e.g., 1-methylxanthine (IX), 1-methylurate (lU)) or combinations of metabolites. Dapsone and sulfamethazine have also been used to phenotype NAT2. 

Klassen, R. Stavric, B. HPLC separation of theophylline, paraxanthine, theobromine, caffeine and other caffeine metabolites in biological fluids. J.Liq.Chromatogr, 1983, 6, 895-906 [plasma milk urine saliva]... 

Van Aerde, P. Moerman, E. Van Severen, R. Braeckman, P. Determination of plasma theophylline by straight-phase high-performance liquid chromatography elimination of interfering caffeine metabolites. J.Chromatogr, 1981, 222, 467-474... 

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... 

In 21 healthy subjects, allopurinol 300 mg daily for 8 days altered the levels of urinary caffeine metabolites of a single 200-mg dose of caffeine. In particular, the metabolic ratio used to determine whether people are fast or slow acetylators was substantially changed. Thus, allopurinol may invalidate the results of phenotyping with the urinary caffeine test. In addition, the caffeine metabolite ratio used to express the activity of the cytochrome P450 isoenzyme CYP1A2 was not stable when allopurinol was used. This interaction is of relevance to research rather than clinical practice. 

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