Study of the demethylation of [1,3,7-Me-13C] caffeine in man using respiratory exchange measurements.

Caffeine was shown to be demethylated both in the rat and in man into dimethyl and monomethyl derivatives. There are no quantitative data on the demethylation process because in man the identified metabolites have not all been quantified, and in addition unidentified polar metabolites have been reported recently both in the rat and in man. To quantify the total demethylation process and to study the use of caffeine as a clinical test to analyse hepatic functions, [1,3,7-Me-13C]caffeine was synthesized and 200 mg was administered orally to volunteers. Expired carbon dioxide was continuously measured and collected in a liquid nitrogen trap and then analysed on a double inlet mass spectrometer. A significant increase of the 13CO2 over the basal value was already observed in the first sample collected 15 minutes after the administration. The 13CO2 enrichment reached a maximum within one hour, exhibited a plateau and after 5 hours decreased slowly to return near the basal value after 24 hours. From 21 to 26% of total 13C administration was recovered in expired CO2 over 24 hours. These percentages corresponded also to a mean rate of demethylation for each methyl group. Thus, [1,3,7-Me-13C]caffeine is a molecule suitable for a breath test. However, it remains to show whether or not P-448 induction stimulates a specific demethylation. From these data a specific enrichment of a methyl group could be decided. The use of a physiological dose of caffeine and the use of stable isotopes constitute a non-invasive and safe technique to study human liver functions.