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 V_max /K_mratio 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_is 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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