Diazepam-omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

Br J Clin Pharmacol. 1996 Aug;42(2):157-62. doi: 10.1046/j.1365-2125.1996.03563.x.


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.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Anti-Anxiety Agents / metabolism*
  • Anti-Ulcer Agents / metabolism*
  • Diazepam / metabolism*
  • Drug Interactions
  • Female
  • Humans
  • Ketoconazole / metabolism
  • Male
  • Microsomes, Liver / metabolism*
  • Middle Aged
  • Omeprazole / metabolism*


  • Anti-Anxiety Agents
  • Anti-Ulcer Agents
  • Omeprazole
  • Diazepam
  • Ketoconazole