Caffeine metabolism in a healthy Spanish population: N ‐Acetylator phenotype and oxidation pathways

We studied the oxidative and N ‐acetylator caffeine metabolic profile in 107 healthy Spanish volunteers. Smokers had significantly higher N‐1‐ and N ‐3‐demethylations activities than nonsmokers ( p = 0.03 and p = 0.02, respectively), and the three caffeine demethylations indexes were strongly correlated with each other ( r > 0.7; p < 0.001). Our in vivo studies suggest that CYP1A2 is involved, at least in part, in the primary N ‐demethylations of caffeine. A non‐normal and possibly bimodal distribution was detected in the xanthine oxidase activity ( p = 0.04), with about 4% of subjects deficient of this metabolic activity. The population exhibited a trimodal distribution of acetylator phenotype determined by use of the 5‐acetylamino‐6‐amino‐3‐methyluracil/1‐methylxanthine ratio (normality test; p = 0.004). Seventy subjects (65.4%) were phenotyped as slow acetylators. The mutated gene frequency was 0.81, which is similar to other white populations. Clinical Pharmacology and Therapeutics (1994) 55, 293–304; doi: 10.1038/clpt.1994.30