Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes |
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Authors: | K. ZOMORODI,& J. B. HOUSTON |
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Affiliation: | Department of Pharmacy, University of Manchester, Manchester, UK |
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Abstract: | 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 Kis 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. |
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Keywords: | omeprazole diazepam omeprazole sulphone human microsomes in vitro metabolism drug interactions CYP3A CYP2C19 |
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