DIAZEPAM-OMEPRAZOLE INHIBITION INTERACTION - AN IN-VITRO INVESTIGATION USING HUMAN LIVER-MICROSOMES

1 The metabolism of diazepam to its primary metabolites 3-hydroxydiaze pam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsom es. 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 mu l min(-1) mg(-1) protein. 2 Inhibition of the two metabolic pathways of diazepa m by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K-i of 201 +/- 89 mu M was obtained for the 3HDZ p athway (K-m/K-i ratio of 3.0 +/- 0.9). 3 Inhibitory effects of omepraz ole sulphone on the 3HDZ and NDZ pathways were also investigated. Omep razole sulphone inhibited both pathways with similar K(i)s of 121 +/- 45 and 188 +/- 73 mu M respectively (K-m/K-i ratios of 5.2 +/- 2.3 and 3.3 +/- 1.5 respectively). 4 These in vitro data provide direct evide nce for cytochrome P450 inhibition as the mechanism for the well docum ented diazepam-omeprazole clinical interaction and indicate that omepr azole sulphone, as well as the parent drug, contribute to the inhibiti on effect.