Increase of cytochrome P450IA2 activity by omeprazole: evidence by the 13C-[N-3-methyl]-caffeine breath test in poor and extensive metabolizers of S-mephenytoin.
Omeprazole has been shown to induce cytochrome P450IA1 and P450IA2 activity in vitro. To reflect cytochrome P450IA2 (CYP1A2) activity in vivo, the 13C-[N-3-methyl]-caffeine breath test was conducted in 18 volunteers: 12 extensive metabolizers, one intermediate metabolizer, and five poor metabolizers of S-mephenytoin. Breath tests were performed before treatment with an oral dose of 40 mg omeprazole, on the seventh day of treatment, and after a 7-day washout period. The mean percentage exhalation of the 13C test dose, as determined by 13CO2 in breath during 8 hours, was 23.0% +/- 8.0% (n = 18) before treatment. The largest increases in exhalation rate of 13CO2 were observed in the poor metabolizers and the intermediate metabolizers (range, 12.8% to 62.9%; median, 38.9%); median area under the plasma concentration-time curves (AUC) of omeprazole was four times higher than in the extensive metabolizers. The change after omeprazole treatment in extensive metabolizers ranged from -9.8% to +47.7% (median, 12.3%; n = 12) of pretreatment values. In both groups exhalation rates of 13CO2 returned to near pretreatment values within the 7-day washout period (24.2% +/- 7.8%; n = 17). Changes in the 13C-caffeine breath test correlated well with both the pretreatment value (R = -0.67, p = 0.003; n = 18) and the plasma AUC of omeprazole (R = 0.61, p = 0.007; n = 18). Therapeutic doses of omeprazole seem to induce CYP1A2 activity in poor metabolizers, whereas they exert minor inducing effects in extensive metabolizers of S-mephenytoin.
Rost
K L
KL
Institute of Clinical Pharmacology, Klinikum Steglitz, Free University of Berlin, Germany.
Brösicke
H
H
Brockmöller
J
J
Scheffler
M
M
Helge
H
H
Roots
I
I
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases; D001944:Breath Tests / Q000379:methods*; D002110:Caffeine / Q000031:analogs & derivatives; D002245:Carbon Dioxide / Q000378:metabolism; D002247:Carbon Isotopes; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009853:Omeprazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype
D002247:Carbon Isotopes; D002245:Carbon Dioxide; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin