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

Abstract

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.