Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation.
OBJECTIVE
To compare the interaction potential of E3810, [(+/-)-sodium 2-[[4-(3-methoxpropoxy)-3-methylpyridin-2-yl]methylsulfinyl] -1H-benzimidazole] a new proton pump inhibitor, and omeprazole with diazepam in relation to S-mephenytoin 4'-hydroxylation status.


METHODS
Fifteen healthy male volunteers consisting of six poor metabolizers and nine extensive metabolizers of S-mephenytoin 4'-hydroxylation participated in the study, where two poor and three extensive metabolizers each as a group were randomly allocated to one of the three different treatment sequences with a 3-week washout period among the three trial phases. Each volunteer received an oral once-daily dose of E3810 (20 mg), omeprazole (20 mg), or placebo for 23 days and an intravenous dose (0.1 mg/kg) of diazepam on posttreatment day 8. Plasma concentrations of diazepam and demethyldiazepam were measured up to 16 days after the administration of diazepam.


RESULTS
Diazepam was more slowly metabolized in the poor metabolizers than in the extensive metabolizers. No significant effects of E3810 and omeprazole on any kinetic parameters of diazepam were observed in the poor metabolizers. In the extensive metabolizers, omeprazole significantly decreased the mean clearance of diazepam and increased its half-life, area under the plasma concentration-time curve, and mean residence time compared with E3810 and placebo (p < 0.05 or 0.01), whereas no changes in these kinetic parameters were observed during the treatment with E3810. Omeprazole significantly increased the mean area under the plasma concentration-time curve (0-16 days) of demethyldiazepam in the extensive metabolizers compared with placebo (p < 0.01), whereas E3810 significantly increased it in the poor metabolizers compared with omeprazole or placebo (p < 0.05).


CONCLUSIONS
The results indicate that E3810 as a substrate goes less toward S-mephenytoin 4'-hydroxylase (CYP2C19) and has a much weaker, if any, potential to interact with diazepam compared with omeprazole.
Ishizaki
T
T
Department of Clinical Pharmacology, International Medical Center of Japan, Tokyo.
Chiba
K
K
Manabe
K
K
Koyama
E
E
Hayashi
M
M
Yasuda
S
S
Horai
Y
Y
Tomono
Y
Y
Yamato
C
C
Toyoki
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles / Q000494:pharmacology*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008617:Mephenytoin / Q000493:pharmacokinetics*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D003708:Nordazepam / Q000097:blood; D009853:Omeprazole / Q000494:pharmacology*; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D012016:Reference Values; D016037:Single-Blind Method
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D003708:Nordazepam; 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; D003975:Diazepam; D008617:Mephenytoin