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Nonlinear kinetics of omeprazole and its metabolites were investigated after treatment with repeated high doses. Extensive metabolizers relating to cytochrome P450 2C19 (CYP2C19) activity received for 1 week either omeprazole at 40 mg/d (n = 14) or 60 mg/d omeprazole twice daily (n = 8). Five poor metabolizers (PMs) received 40 mg/d for 1 week. Comparison of omeprazole plasma kinetics between extensive metabolizers (EMs) and PMs after 40-mg treatment revealed a dominant role of CYP2C19 over cytochrome P450 3A CYP3A in omeprazole metabolism. Comparing the omeprazole doses of 40 mg and 60 mg in eight EMs on day 7 of treatment showed that CYP2C19-dependent plasma clearance of omeprazole and omeprazole sulfone was reduced from 19.0 to 8.4 L/h (P < .001) and from 19.8 to 9.2 L/h (P = .012), respectively. Similarly, formation half-life of 5'-hydroxyomeprazole increased from 0.58 to 1.45 hours (P = .025) with the higher dose. CYP3A-dependent metabolic routes remained unaffected. Thus, high-dose treatment with omeprazole uncovers saturation kinetics for CYP2C19 pathways in EMs, and CYP3A becomes the predominant enzyme of omeprazole elimination. Moreover, these individuals may be at risk for side effects due to high omeprazole concentrations if high-dose omeprazole treatment is combined with drugs inhibiting CYP3A activity.

Omeprazole induces hepatic cytochrome P-4501A2. In a previous study this effect was shown to be significant in vivo in 6 poor metabolizers, including 1 intermediate metabolizer, but not in 12 extensive metabolizers of S-mephenytoin after 7 days of treatment with 40 mg/day omeprazole. In this study, the specificity of the inducing potential of omeprazole was investigated in these volunteers. Furthermore, in eight of the extensive metabolizers the dose-dependence of cytochrome P-450 1A2 induction was evaluated. Cytochrome P-450 1A2 activity was monitored by means of the 13C-[N3-methyl]caffeine breath test and by means of plasma caffeine clearance before omeprazole treatment with 120 mg/day, on the seventh day of dosage and after a 7-day washout. Omeprazole plasma concentration was measured. Results were compared with those after 40 mg. gamma-Glutamyltransferase activity in serum, as well as urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, were measured on the same study days in all study groups (n = 26). In the eight extensive metabolizers the breath test indicated a dose-dependent increase of cytochrome P-450 1A2 activity of 8.5% +/- 15.0% (40 mg, mean +/- SD, NS) and 27.2% +/- 16.5% (120 mg, p = 0.002). Caffeine clearance was increased by 31.6% +/- 20.7% (p < 0.001) with the higher dose. None of the study groups exhibited a significant increase of gamma-glutamyltransferase activity or urinary excretion of D-glucaric acid or 6 beta-hydroxycortisol. This was in contrast to the phenobarbital-type induction observed after treatment with antiepileptic drugs. Induction by omeprazole seems to be restricted to cytochrome P-450 1A enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)