Time-dependent amplified pharmacokinetic and pharmacodynamic responses of rabeprazole in cytochrome P450 2C19 poor metabolizers.
OBJECTIVE
To determine the pharmacokinetic and pharmacodynamic rationale for the optimum regimen of rabeprazole in the treatment of Helicobacter pylori infection in patients who are cytochrome P450 (CYP) 2C19 poor metabolizers or extensive metabolizers.


METHODS
Prospective, multiple-dose pharmacokinetic and pharmacodynamic study.


METHODS
University-affiliated medical center in Taiwan.


METHODS
Twelve healthy volunteers (aged 20-30 yrs) who were identified as CYP2C19 poor metabolizers (six subjects) or extensive metabolizers (six).


METHODS
Each subject received rabeprazole 20 mg twice/day for 3 consecutive days and once/day on the fourth day.


RESULTS
Pharmacokinetic and pharmacodynamic parameters were compared between CYP2C19 poor and extensive metabolizers on day 1 and day 4 of dosing. The mean +/- SD values of area under the concentration-time curve of rabeprazole and rabeprazole thioether were significantly higher in poor metabolizers than in extensive metabolizers on day 1 (5357 +/- 883 vs 1131 +/- 512 ng x hr/ml and 1703 +/- 432 vs 561 +/- 358 ng x hr/ml, respectively; p<0.001) and on day 4 (5601 +/- 669 vs 1619 +/- 778 ng x hr/ml and 1914 +/- 378 vs 511 +/- 360 ng x hr/ml, respectively; p<0.001). However, no significant difference was noted between day 1 and day 4 of dosing within the same genotype groups. Only CYP2C19 poor metabolizers had significantly higher plasma gastrin levels on day 4 compared with those levels on day 1 (p<0.05). The pharmacokinetic-pharmacodynamic relationship of rabeprazole appears to be time dependent.


CONCLUSIONS
The pharmacokinetic and pharmacodynamic data suggest that CYP2C19 poor metabolizers might be subject to advantageous conditions, especially after day 4, for treating H. pylori infection with rabeprazole.
Lin
Chun-Jung
CJ
Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei.
Yang
Jyh-Chin
JC
Uang
Yow-Shieng
YS
Chern
Herng-Der
HD
Wang
Teh-Hong
TH
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000046:Academic Medical Centers; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001944:Breath Tests; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005755:Gastrins / Q000097:blood; D005838:Genotype; D016481:Helicobacter Infections / Q000175:diagnosis / Q000201:enzymology; D016480:Helicobacter pylori / Q000302:isolation & purification; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009853:Omeprazole / Q000031:analogs & derivatives; D011446:Prospective Studies; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D013624:Taiwan; D013997:Time Factors
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D005755:Gastrins; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole