Omeprazole weakly inhibits CYP1A2 activity in man

Background and objectives: Omeprazole is an inducer of human cytochrome P45 0 1 A (CYP1A) enzymes, but shows inhibitory effects on CYP2C19 and CYP3A4. In this study, a potential inhibitory effect of omeprazole on caffeine meta bolism, a validated CYP1A2 marker, was examined. Methods: A randomized, bal anced crossover single-dose study was conducted in 16 healthy volunteers co mprising 12 extensive (EM) and 4 poor metabolizers (PM) for CYP2C19. All vo lunteers received a 40 mg omeprazole dose or placebo 0.5 h prior to caffein e 3 mg/kg body weight. Six EMs were re-tested with 80 mg of omeprazole. In vitro, effects of omeprazole on caffeine N3-demethylation were determined i n human liver microsomes. Results: In vivo, nonparametric point estimates ( 90% confidence intervals) for the ratios of caffeine pharmacokinetics with/ without co-administration of the 40 mg omeprazole dose were: AUC 1.08 (1.04 - 1.13), MRT 1.09 (0.99 - 1.19), and plasma ratio of paraxanthine/caffeine 6 h post-dose 0.91 (0.80 - 1.00). Inhibition of caffeine N3-demethylation by omeprazole was slightly more pronounced in PM than in EM of CYP2C19. Est imates for the 80 mg omeprazole dose were: AUC 1.12 (1.05 - 1.18), MRT 1.18 (1.07 - 1.30), and paraxanthine/caffeine ratio 0.83 (0.74 - 0.94). In vitr o, omeprazole was mainly a competitive CYP1A2 inhibitor with Ki values of a round 150 mu M. Conclusions: Omeprazole exerts a concentration-dependent in hibition of CYP1A2 activity in man. However, even after single oral doses u p to 80 mg, this effect is weak and without clinical relevance.