title: Diazepam-omeprazole inhibition interaction: an in vitro investigation using human liver microsomes.
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 Vmax/Km ratio of 0.50-7.26 microliters 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 Ki of 201 +/- 89 microM was obtained for the 3HDZ pathway (Km/Ki 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 microM respectively (Km/Ki 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.
authors.affiliation: Department of Pharmacy, University of Manchester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Zomorodi
authors.forename: J B
authors.initials: JB
authors.lastname: Houston
mesh_terms: D000328:Adult; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D000897:Anti-Ulcer Agents / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D009853:Omeprazole / Q000378:metabolism*
chemical_list: D014151:Anti-Anxiety Agents; D000897:Anti-Ulcer Agents; D009853:Omeprazole; D003975:Diazepam; D007654:Ketoconazole