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Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes
Author(s) -
ZOMORODI K.,
HOUSTON J. B.
Publication year - 1996
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1996.03563.x
Subject(s) - omeprazole , microsome , diazepam , chemistry , pharmacology , metabolism , cytochrome p450 , drug metabolism , ic50 , in vitro , biochemistry , medicine
1 The metabolism of diazepam to its primary metabolites 3‐hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V max /K m ratio of 0.50–7.26 μl min −1 mg −1 protein. 2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K i of 201±89 μm was obtained for the 3HDZ pathway ( K m /K i ratio of 3.0±0.9). 3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K i s of 121±45 and 188±73 μm respectively ( K m /K i ratios of 5.2±2.3 and 3.3±1.5 respectively). 4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam‐omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.