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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
Author(s) -
Ishizaki Takashi,
Chiba Kan,
Manabe Kyoko,
Koyama Eriko,
Hayashi Masahiro,
Yasuda Sanae,
Horai Yukio,
Tomono Yoshiro,
Yamato Chiyuki,
Toyoki Takaaki
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90193-0
Subject(s) - omeprazole , mephenytoin , diazepam , pharmacology , cyp2c19 , chemistry , placebo , anesthesia , medicine , metabolism , cytochrome p450 , biochemistry , alternative medicine , pathology
Objective To compare the interaction potential of E3810, [(±)‐sodium 2‐[[4‐(3‐methoxypropoxy)‐3‐methylpyridin‐2‐yl]methylsulfinyl]‐1H‐benzimidazole] a new proton pump inhibitor, and omeprazole with diazepam in relation to S ‐mephenytoin 4′‐hydroxylation status. Study design 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). Conclusion 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. Clinical Pharmacology & Therapeutics (1995) 58 , 155–164; doi: