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.

This study demonstrated the feasibility of utilizing the (3-13C-methyl) caffeine breath test (CBT) in children and adolescents, and examined the effect of gender, age, and puberty on the CBT. The CBT, expressed as the 2-hour accumulative exhalation of labeled CO(2) (2-hour CO(2)), was compared to the CBT results in the adult. The 2-hour CO(2) values were higher in the children than the adult, and the decrease in the CO(2) values occurred in males during late puberty and in females during early puberty.

1. Rats and mice have a greater capacity than dogs or humans to N-demethylate the quaternary ammonium compound, N-methylnaltrexone. 2. In dogs, following the i.v. administration of N-[14C-methyl]methylnaltrexone, 50% of the radioactivity was excreted in the urine and an additional 30% in the faeces within 120 h. 3. In humans following the i.v. administration of 14C-N-methylnaltrexone, 40-60% of the radioactivity was excreted in the urine within the first 24 h. The plasma radioactivity-time curves indicated a biphasic decay and a short distribution phase between 6 and 9 min. with a longer elimination phase between 238 and 1320 min.