Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotypes.
BACKGROUND
S-mephenytoin 4'-hydroxylase (CYP2C19) catalyses the metabolism of rabeprazole to some extent. Based on the metabolic and pharmacokinetic differences among other proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole, rabeprazole appears to be the least affected proton pump inhibitor by the CYP2C19-related genetic polymorphism.


OBJECTIVE
To determine whether the pharmacodynamic effects of rabeprazole on intragastric pH and serum gastrin levels, and its pharmacokinetics depend on the CYP2C19 genotype status.


METHODS
Eighteen healthy subjects, whose CYP2C19 genotype status was previously determined, participated in the study. They consisted of six each of homozygous extensive metabolisers (homo EMs), heterozygous extensive metabolisers (hetero EMs), and poor metabolisers (PMs). Helicobacter pylori status was determined by serology. After a single oral dose of 10 mg or 20 mg rabeprazole or water only (baseline data), intragastric pH values were monitored for 24 h. Plasma levels of rabeprazole and serum gastrin were also measured for 24 h post-dose.


RESULTS
Five homo EM, six hetero EM and four PM subjects were H. pylori-negative. After rabeprazole administration, significant differences in intragastric mean pH values, serum gastrin AUC(0-24) and plasma levels of rabeprazole were observed among the three different genotype groups.


CONCLUSIONS
The pharmacodynamic effects of rabeprazole and its pharmacokinetics depend on the CYP2C19 genotype status.
Horai
Y
Y
Clinical Research Center of Japan, Eisai Co., Ltd, Tokyo, Japan. y-horai@hhc.eisai.co.jp
Kimura
M
M
Furuie
H
H
Matsuguma
K
K
Irie
S
S
Koga
Y
Y
Nagahama
T
T
Murakami
M
M
Matsui
T
T
Yao
T
T
Urae
A
A
Ishizaki
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000284:Administration, Oral; D000328:Adult; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005745:Gastric Acidity Determination; D005755:Gastrins / Q000097:blood; D005838:Genotype; D016481:Helicobacter Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009853:Omeprazole / Q000031:analogs & derivatives; D011110:Polymorphism, Genetic; D064750:Rabeprazole
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D005755:Gastrins; D064750:Rabeprazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole