K. Zomorodi et Jb. Houston, DIAZEPAM-OMEPRAZOLE INHIBITION INTERACTION - AN IN-VITRO INVESTIGATION USING HUMAN LIVER-MICROSOMES, British journal of clinical pharmacology, 42(2), 1996, pp. 157-162
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.