The caffeine CO2 breath test: Dose response and route of N-demethylation in smokers and nonsmokers

Abstract

The optimal conditions for performing the caffeine CO2 breath test (CBT) were investigated in smokers and nonsmokers. Caffeine labeled with 13C or 14C in all three (1, 3, and 7) methyl groups or specifically in the 1-, 3-, or 7-methyl groups were orally administered to healthy adults and the expiration of labeled CO2 was measured for 8 or 24 hr. The absolute rate of labeled CO2 excretion from trilabeled caffeine was proportional to the dose up to 3 mg/kg in all subjects. In smokers, the rate of labeled CO2 excretion averaged twice that in nonsmokers at all doses. A correlation was observed between the 2-hr cumulative CO2 excretion from trilabeled caffeine and the apparent oral metabolic clearance rate (MCR) of caffeine (R = 0.90). Monolabeled CBTs in smokers and nonsmokers demonstrated that 80% +/- 4% of labeled CO2 expired in the breath during the first 2 hr of a trilabeled CBT was derived from the 3 position; at 6 to 8 hr equal amounts were derived from the 3 and 7 positions. Little N-demethylation was observed from the 1 position at any time during the 8-hr test. The results indicate that the 2-hr cumulative excretion of labeled CO2 could be used to accurately predict the metabolic clearance rate of caffeine is the best CBT parameter for detecting the effect of smoking on caffeine N-demethylation. The data suggest that the primary routes of caffeine metabolism are 3-N-demethylation and ring hydroxylation and confirm that caffeine metabolites are N-demethylated primarily in the 3 and 7 positions.

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

“…For the CYP1A2 substrate [ 13 C]-caffeine, Park et al observed a significant correlation between 1 h single DOB 13 CO 2 / 12 CO 2 ratios and plasma [ 13 C]-caffeine clearance [132]. These results were in agreement with previous studies, in which excellent correlations between caffeine breath test results and caffeine clearance were found [133][134][135][136].…”

The Caffeine Breath Test and Caffeine Urinary Metabolite Ratios in the Michigan Cohort Exposed to Polybrominated Biphenyls: A Preliminary Study

“…The 2-hr accumulative exhalation of labeled CO2 was the CBT parameter calculated, since it is the best monitor of caffeine clearance in the adult (20). The CBT data from the Michigan PBB cohort was compared to the CBT data from our control groups of healthy urban Ilinois adult smokers or nonsmokers without a history of PBB exposure (20,24).…”

“…The caffeine substrate used to monitor caffeine 3-Ndemethylation in the CBT was [3-13C-methyl] caffeine (99% 3C) synthesized by Cambridge Isotopes (Cambridge, MA) or by A. N. Kotake (20). The labeled caffeine dose, 3 mg/kg (up to a maximal dose of 250 mg), was dissolved in 20 mL of sterile water and ingested by the volunteers, followed by ingestion of a 20-mL water wash of the container.…”

“…P450I-dependent caffeine 3-N-demethylase activity was monitored by the caffeine breath test (CBT) (20), and 7-N-demethylase activity was monitored by the caffeine urinary metabolite ratio (CMR) (21).…”

Validity of the 13C–Caffeine Breath Test As A Noninvasive, Quantitative Test of Liver Function

“…30,31 It generally has been accepted that the 2-hour cumulative exhalation of labeled CO 2 represents the best parameter of caffeine clearance in the adult. 32 Our data suggest that a single 1-hour measure is equally informative and simplifies the test. Moreover, we have shown that this parameter is highly reliable in terms of its reproducibility in subjects with a normal or cirrhotic liver.…”