Accelerated caffeine metabolism after omeprazole treatment is indicated by urinary metabolite ratios: coincidence with plasma clearance and breath test.
BACKGROUND
Omeprazole has previously been shown to induce hepatic cytochrome P4501A2 activity, as evidenced by an accelerated N-3-demethylation in the 13C-[N-3-methyl]-caffeine breath test. In this study we investigated whether the inducing potency of omeprazole can be quantified by the determination of urinary caffeine metabolite ratios, which are based on the urinary excretion of N-3-demethylated metabolites. These data were also compared with changes in plasma clearance.


METHODS
Twelve healthy volunteers were phenotyped as extensive metabolizers of S-mephenytoin and received seven daily doses of 40 mg omeprazole; eight of these were also treated with 120 mg/day. Moreover, six poor metabolizers were treated with 40 mg/day omeprazole. Three different urinary caffeine metabolite ratios were evaluated from urine samples collected between 5 and 8 hours after caffeine intake.


RESULTS
The extensive metabolizers had a slight and nonsignificant acceleration between 7.8% and 17.0% after 40 mg omeprazole by the urinary ratios. However, treatment with 120 mg/day led to highly significant increases ranging from 25.0% to 32.1% (p < 0.002) in this group. Poor metabolizers responded with the highest increases of 40.2% to 41.2%. There was a good correlation between these parameters and the caffeine breath test, as well as the plasma caffeine clearance.


CONCLUSIONS
The study showed an equivalent caffeine N-3-demethylation activity by all evaluation methods. The three urinary caffeine metabolite ratios sampled at the convenient interval of 5 to 8 hours after administration showed the dependence of CYP1A2 induction by omeprazole on the dose and genetic trait of S-mephenytoin hydroxylase.
Rost
K L
KL
Institute of Clinical Pharmacology, Klinikum Steglitz, Free University of Berlin, Germany.
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D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001944:Breath Tests; D002110:Caffeine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010641:Phenotype; D013806:Theophylline / Q000097:blood / Q000378:metabolism / Q000652:urine*; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine
D014527:Uric Acid; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2; D010089:Oxidoreductases, N-Demethylating; D009853:Omeprazole; C021183:1,7-dimethylxanthine; D008617:Mephenytoin; C053084:1,7-dimethyluric acid