Omeprazole weakly inhibits CYP1A2 activity in man.
OBJECTIVE
Omeprazole is an inducer of human cytochrome P450 1A (CYP1A) enzymes, but shows inhibitory effects on CYP2C19 and CYP3A4. In this study, a potential inhibitory effect of omeprazole on caffeine metabolism, a validated CYP1A2 marker, was examined.


METHODS
A randomized, balanced crossover single-dose study was conducted in 16 healthy volunteers comprising 12 extensive (EM) and 4 poor metabolizers (PM) for CYP2C19. All volunteers received a 40 mg omeprazole dose or placebo 0.5 h prior to caffeine 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 in human liver microsomes.


RESULTS
In vivo, non-parametric 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. Estimates 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 vitro, omeprazole was mainly a competitive CYP1A2 inhibitor with K(i) values of around 150 microM.


CONCLUSIONS
Omeprazole exerts a concentration-dependent inhibition of CYP1A2 activity in man. However, even after single oral doses up to 80 mg, this effect is weak and without clinical relevance.
Rost
K L
KL
PAREXEL Institute of Clinical Pharmacology, Klinikum Westend, Berlin, Germany.
Fuhr
U
U
Thomsen
T
T
Zaigler
M
M
Brockmöller
J
J
Bohnemeier
H
H
Roots
I
I
D000328:Adult; D001667:Binding, Competitive; D015415:Biomarkers / Q000097:blood; D002110:Caffeine / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009853:Omeprazole / Q000008:administration & dosage*; D016037:Single-Blind Method; D013806:Theophylline / Q000097:blood
D015415:Biomarkers; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D002110:Caffeine; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2; D009853:Omeprazole; C021183:1,7-dimethylxanthine