Heterogeneity in Assessing Self-Reports of Caffeine Exposure
Michael B. BrackenElizabeth W. TricheLaura M. GrossoKaren HellenbrandKathleen BelangerBrian P. Leaderer
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Background. Coffee and its metabolite caffeine are widely studied for their health effects but with inconclusive results. Caffeine is particularly difficult to assess, and therefore we explore heterogeneity of caffeine exposure. Methods. We categorized caffeine exposure among 2,478 pregnant women in southern New England during 1996–2000 by the traditional laboratory-based methods of M. Bunker and M. McWilliams. A subsample was examined to ascertain caffeine levels of brewed or purchased beverages actually consumed. Results. More than half (56.6%) of women drank coffee since becoming pregnant. Serving sizes ranged from 2 to 32 oz and are considerably larger than laboratory standards, which are typically 8–10 oz, as compared with the standard of 5 to 6 oz. Conversely, caffeine content per serving of coffee was one-third the laboratory standard, eg, 100 mg caffeine compared with 300 mg for a 10-oz cup. Tea brewed more than 3 minutes contained 42 mg caffeine as compared with the standard of 94 mg. When the amount of caffeine actually consumed was measured, one-quarter (24.8%) of subjects traditionally classified as consuming 300+ gm caffeine daily were reclassified as consuming 150–299 mg. Conclusion. Misclassification of caffeine consumption increases difficulty in identifying health effects from caffeine. Some combination of more precise consumption data and a biomarker such as paraxanthine may more precisely estimate exposure.Keywords:
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The relationship between self‐reports of caffeine ingestion on two occasions and measured plasma concentrations of caffeine and its major metabolites was examined. A subject population [ 25 men and 25 women, age 20–45 years (mean: 28.7 yr) ] that was enrolled in a benzodiazepine pharmacokinetic study underwent general medical screening on two occasions, each including detailed caffeine histories. Before beginning their scheduled study, plasma samples were obtained and evaluated by HPLC for caffeine, paraxanthine, theophylline, and theobromine. These values were compared with estimates of caffeine consumption in mg/day generated from both histories. There was no significant difference between plasma levels of caffeine, metabolites, or caffeine plus metabolites for categories corresponding to reports of low, intermediate or high caffeine use. A self‐reported caffeine consumption of greater than 300 mg/day (high) did correlate, however, with a significant smoking history. The authors conclude that self‐reports of caffeine ingestion do not accurately reflect acute exposure, and that if caffeine use is of importance in a given setting, reports should be confirmed by biochemical means .
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Caffeine is metabolized extensively (on average 80%) to paraxanthine. With regular caffeine consumption, average serum levels of paraxanthine are two thirds those of caffeine. Both caffeine and paraxanthine competitively and nonselectively inhibit adenosine receptors in vitro. To examine the contribution of paraxanthine to the pharmacologic activity of caffeine, we administered to 12 subjects in a crossover design oral caffeine (2 or 4 mg/kg) versus placebo or oral paraxanthine (same dose as caffeine) versus placebo, each after 3 days of methylxanthine abstinence. Both caffeine and paraxanthine significantly increased diastolic blood pressure, plasma epinephrine levels, and free fatty acids. Caffeine and paraxanthine produced a similar magnitude of response at 4 mg/kg; however, caffeine appeared to produce greater responses than paraxanthine at 2 mg/kg. Caffeine and paraxanthine have similar sympathomimetic actions. The activity of paraxanthine needs to be considered in understanding the clinical pharmacology of caffeine, particularly with chronic, repetitive caffeine consumption. Clinical Pharmacology & Therapeutics (1995) 58, 684–691; doi:
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Theophylline peak plasma concentration of over 170 ng/ml average was observed when 300 mg of caffeine, equivalent to 2-3 cups of coffee, was administered to humans. This peak level was not observed until at least 7 hr post administration. Accumulation of caffeine, with its subsequent metabolism to theophylline, in patients, who consume average quantities of caffeine-containing beverages relative to those patients who avoid such drinks could interfere with bioavailability studies in normal volunteers. However, it may account for only a small portion of the variable clinical effects associated with aminophylline administration.
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Several procedures to monitor CYP1A2 activity in vivo by the use of caffeine as a probe have been proposed. They comprise caffeine clearance, based on both plasma and saliva concentrations, urinary metabolite ratios, the 13C-caffeine breath test, and the paraxanthine/caffeine ratio in plasma. The latter method is fast, simple, economical and restricted to one sampling point. In this study, we retrospectively analysed four clinical trials comprising 78 subjects to validate the use of the paraxanthine/caffeine ratios in plasma and saliva for CYP1A2 activity. The validation was done by correlation of these ratios to the systemic caffeine clearance as a reference method. Additionally, urinary metabolite ratios and the caffeine breath test were included in the analysis. The paraxanthine/caffeine ratios in plasma and saliva preferably 5-7 h after administration of caffeine most closely resembled systemic caffeine clearance with correlation coefficients typically higher than r = 0.85. An equation to estimate systemic caffeine clearance from the paraxanthine/caffeine ratios taken at any time within 3-7 h postdose was developed. Correlations of systemic clearance with urinary metabolite ratios and the caffeine breath test were less reliable both in this investigation and in the literature. In conclusion, the paraxanthine/caffeine ratios in plasma and saliva appear a valid and inexpensive method of assessing CYP1A2 activity in vivo. Apparent distribution of CYP1A2 activity for all healthy subjects appeared bimodal in nonsmokers (n = 29) and smokers (n = 17).
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Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down, and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N = 20 participants and three within-subject conditions: caffeine (150 mg caffeine × 3/day × 10 days), placebo (150 mg mannitol × 3/day × 10 days), and acute caffeine deprivation (caffeine × 9 days, afterward placebo × 1 day). On day 10, we determined the course of salivary caffeine and paraxanthine using liquid chromatography-mass spectrometry coupled with tandem mass spectrometry. We assessed gray matter (GM) intensity and cerebral blood flow (CBF) after acute caffeine deprivation as compared to changes in the caffeine condition from our previous report. The results indicated that levels of paraxanthine and caffeine remained high and were carried overnight during daily intake, and that the levels of paraxanthine remained elevated after 24 h of caffeine deprivation compared to placebo. After 36 h of caffeine deprivation, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 h of abstinence. They also suggest investigating the consequences of a paraxanthine accumulation during daily caffeine intake.
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The caffeine content of all tea or coffee beverages consumed by 17 healthy adults over 24 hours was measured. Plasma caffeine, theophylline, theobromine, and paraxanthine concentrations were determined over the same 24 hours. The average caffeine content per drink was 60.4 ± 21.8 mg for instant coffee (14-fold range), 80.1 ± 19.2 mg for brewed coffee (2.8-fold range), and 28.8 ± 13.7 mg for tea (5.5-fold range). The number of drinks of coffee and tea consumed was a poor index of actual caffeine intake (r2= 0.42). Caffeine intake correlated poorly with the 24-hour average caffeine concentration (r2= 0.41), but there was a very good correlation between a single plasma caffeine concentration measured at 5 PM and the 24-hour average concentration (r2= 0.94). The same was true for paraxanthine (r2= 0.86). Paraxanthine accounted for 67.3% of the total dimethylxanthines in plasma, while theobromine and theophylline accounted for 24.4% and 8.3%, respectively. Mean caffeine clearance was 1.2 ± 0.3 ml/min/ kg. Plasma caffeine concentration before the first drink in the morning correlated very poorly with caffeine clearance (r2= 0.07), even when adjusted for caffeine intake (r2= 0.21). Clinical Pharmacology and Therapeutics (1986) 39, 54–59; doi:10.1038/clpt.1986.10
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Abstract Objectives To investigate the utility of metrics of CYP1A2 activity using caffeine as a probe, and saliva and plasma sampling with or without a 24-h caffeine abstinence. Methods This was a cross-over pharmacokinetic study in 30 healthy male subjects who received a single oral 100 mg caffeine dose after 24-h caffeine abstinence or after maintaining their regular caffeine intake (no caffeine abstinence). Serial blood and saliva samples were collected simultaneously over 24 h. Caffeine and paraxanthine concentrations were measured using a validated HPLC assay. Key findings There was a strong correlation between the paraxanthine/caffeine AUC0–24 ratio (reference metric) and the paraxanthine/caffeine concentration (Ct) ratio at 4 h (C4) in both saliva and plasma (r ≥ 0.75). The paraxanthine/caffeine AUC0–24 ratio in plasma and saliva did not differ between the 24-h caffeine abstinence and the no abstinence period (P > 0.05). The optimal paraxanthine/caffeine Ct that correlated with the plasma paraxanthine/caffeine AUC0–24 ratio in the 24-h abstinence period was 2 and 4 h (r = 0.88) in plasma, and 4 and 6 h in saliva (r = 0.70), while it was the saliva 4 h time-point in the no abstinence period (r = 0.78). Conclusions The saliva paraxanthine/caffeine concentration ratio at 4 h was a suitable metric to assess CYP1A2 activity after oral administration of caffeine without the need for 24-h caffeine abstinence.
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Caffeine and theophylline inhibited the activity of rat liver glutamate dehydrogenase (GDH), but not that of beef liver GDH, in forward and reverse directions of the enzyme reaction. In the forward direction, approximately 16 mM caffeine or 16 mM theophylline inhibited 50 per cent of the rat liver GDH activity (I50); while in the reverse direction, the I50 of caffeine and theophylline was 15 mM and 8 mM, respectively. The inhibition produced by caffeine was cooperative in both directions, while that of theophylline was negatively cooperative in the forward direction and non-cooperative in the reverse. However, ADP reduced the inhibitory effect of caffeine and theophylline to the extent of 40% and 80%, respectively. The Ki values obtained for caffeine and theophylline were different in the presence of various concentrations of substrates and coenzymes. Based upon these data, we presume that certain subtle changes occurring in the conformation of the rat liver GDH (probably at the ADP/NADH site) in comparison with those of the beef liver GDH may be responsible for its inhibition by caffeine and theophylline.
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The concentrations of caffeine and its metabolites, dimethylxanthines, in the plasma and saliva were determined in order to clarify the metabolic capacity of caffeine in pregnant women. After taking caffeine-free diet for 3 d, caffeine (3 mg/kg) was orally administered to 6 healthy volunteers. The concentrations of caffeine and dimethylxanthines, i.e. theobromine, paraxanthine and theophylline in the plasma and saliva were measured. The concentrations in the saliva showed positive relationships to those in the plasma for both caffeine and paraxanthine. There was a linear relationship between the plasma clearance of caffeine and the molar concentration ratio of paraxanthine to caffeine in the saliva at 6 h after oral administration of caffeine. The concentration of caffeine in the saliva from pregnant women was higher than 1.3 μg/ml at 1 h after taking one or three cups of coffee or green tea without restriction. These results indicate that the plasma levels of caffeine and paraxanthine can be predicted from the saliva levels of caffeine and paraxanthine. Moreover, it would be possible to estimate the plasma clearance or metabolic capacity of caffeine from the molar concentration ratio of paraxanthine to caffeine in the saliva.
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In two cases of caffeine overdose, the elimination of caffeine appeared to be non-linear. Measurements of theophylline concentrations after caffeine overdose were method-dependent. After caffeine overdose, quantitation of caffeine is not clinically indicated, because of the variable correlation between concentration and toxic effects. Our data suggest that the measurement of theophylline concentrations after caffeine overdose is also not clinically indicated, and may be misleading if a nonspecific method is used.
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