Acid-suppressive effects of rabeprazole, omeprazole, and lansoprazole at reduced and standard doses: a crossover comparative study in homozygous extensive metabolizers of cytochrome P450 2C19.
OBJECTIVE
To improve clinical outcomes of the initial therapy for gastroesophageal reflux disease, intragastric pH should be above 4.0 for more than 20 hours a day (83.3%) and nocturnal gastric acid breakthrough, defined as 60 continuous minutes of intragastric pH below 4.0 at night, should be inhibited. A "step-down" therapy sometimes fails because of insufficient acid suppression. Therefore we compared the acid-suppressive effects of proton pump inhibitors.


METHODS
This was a prospective, randomized, open-label, 8-way crossover study. In 9 healthy Helicobacter pylori-negative cytochrome P450 (CYP) 2C19 homozygous extensive metabolizers, intragastric pH was measured for 24 hours on day 7 of treatment with rabeprazole, omeprazole, and lansoprazole orally administered once daily at reduced and standard doses.


RESULTS
Compared with baseline data (7% [range, 5%-20%]), the median values of the 24-hour percent of time that intragastric pH was above 4.0 significantly increased but did not exceed 83.3% under any of the 7 regimens, which were as follows: 10 mg rabeprazole (51% [range, 28%-78%], P < .01), 20 mg rabeprazole (59% [range, 36%-83%], P < .01), 10 mg omeprazole (26% [range, 4%-33%], P < .05), 20 mg omeprazole (48% [range, 31%-73%], P < .01), 40 mg omeprazole (62% [range, 47%-87%], P < .01), 15 mg lansoprazole (34% [range, 5%-51%], P < .05), and 30 mg lansoprazole (56% [range, 20%-76%], P < .05). Significant differences were observed among 10, 20, and 40 mg omeprazole (10 mg versus 20 mg, P < .01; 10 mg versus 40 mg, P < .01; and 20 mg versus 40 mg, P < .05) and between 15 and 30 mg lansoprazole (P < .01), whereas no significant difference was observed between 10 and 20 mg rabeprazole. Nocturnal gastric acid breakthrough was observed under all regimens.


CONCLUSIONS
Rabeprazole, omeprazole, and lansoprazole, given once daily at standard doses, cannot be expected to achieve ideal acid suppression for the initial therapy for gastroesophageal reflux disease in Helicobacter-negative CYP2C19 homozygous extensive metabolizers. Rabeprazole 10 mg may be appropriate for step-down therapy.
Shimatani
Tomohiko
T
Department of General Medicine, Hiroshima University Hospital, Department of Geriatric Health Sciences, Graduate School of Health Sciences, Hiroshima University, Hiroshima, Japan. tshima@hiroshima-u.ac.jp
Inoue
Masaki
M
Kuroiwa
Tomoko
T
Xu
Jing
J
Mieno
Hiroshi
H
Nakamura
Masuo
M
Tazuma
Susumu
S
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004311:Double-Blind Method; D005745:Gastric Acidity Determination; D005838:Genotype; D016481:Helicobacter Infections / Q000378:metabolism; D016480:Helicobacter pylori; D006801:Humans; D006863:Hydrogen-Ion Concentration; D064747:Lansoprazole; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009853:Omeprazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011446:Prospective Studies; D064750:Rabeprazole
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D064747:Lansoprazole; D064750:Rabeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole