Specific and dose-dependent enzyme induction by omeprazole in human beings

• Published in: Hepatology (Baltimore, Md.) Vol. 20; no. 5; p. 1204
• Main Authors: Rost, K L, Brösicke, H, Heinemeyer, G, Roots, I
• Format: Journal Article
• Language: English
• Published: United States 01.11.1994
• Subjects: Absorption; Adolescent; Adult; Aged; Aged, 80 and over; Caffeine - metabolism; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System - metabolism; Dose-Response Relationship, Drug; Enzyme Induction - drug effects; Female; gamma-Glutamyltransferase - blood; Glutarates - urine; Half-Life; Humans; Hydrocortisone - analogs & derivatives; Hydrocortisone - urine; Male; Mephenytoin - metabolism; Methylation - drug effects; Middle Aged; Omeprazole - pharmacology; Oxidoreductases - metabolism
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840200516

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.