Specific and dose-dependent enzyme induction by omeprazole in human beings.
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)
Rost
K L
KL
Institute of Clinical Pharmacology, Klinikum Steglitz, Free University of Berlin, Germany.
Brösicke
H
H
Heinemeyer
G
G
Roots
I
I
D000042:Absorption; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002110:Caffeine / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005977:Glutarates / Q000652:urine; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008875:Middle Aged; D009853:Omeprazole / Q000494:pharmacology*; D010088:Oxidoreductases / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000097:blood
D005977:Glutarates; D002110:Caffeine; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2; D005723:gamma-Glutamyltransferase; C035736:glutaric acid; D009853:Omeprazole; D008617:Mephenytoin; D006854:Hydrocortisone