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 m ratio of 0.50-7.26 ml 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 m 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 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 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.Keywords omeprazole diazepam omeprazole sulphone human microsomes in vitro metabolism drug interactions CYP3A CYP2C19

Role of cytochrome P450 in drug interactions

“…The dose of metoprolol should be reduced when propafenone is also given [ 70 ]. Similar drug-drug interactions are seen in the combined administration of thioridazine and propranolol (CYP2D6) [ 71 ], fluoxetine and desipramine (CYP2D6) [ 72 ], omeprazole and diazepam (CYP2C19) [ 73 - 75 ], tolbutamide and phenytoin (CYP2C9) [ 32 ], and diltiazem and cyclosporin (CYP3A) [ 76 - 78 ].…”

Assessment of antifungal effect of omeprazole on Candida Albicans

“…and it was demonstrated that in vitro efficiency on Candida spp. was reduced by increasing antifungal dosesm (Wallmark et al, 1983;Whitley-Williams, 2006;Zomorodi and Houston, 1996). Sümer and her colleagues (2005) examined the efficiency of omeprazole on C. albicans and they observed that most of the strains of Candida spp.…”

Effects of multiple-dose esomeprazole and pantoprazole on diazepam pharmacokinetic profile and pharmacodynamic effects on cognitive and psychomotor function in healthy volunteers

“…Proton pump inhibitors and benzodiazepinesaref requentlyt aken concomitantlyin dailyr outine clinical practicef ordifferentpurposes.Relevantdrug-drugi nteractionsmayoccur.The interaction potentialo fPPIs hasbeen intensivelys tudied [3,4].All PPIsarem etabolized in the liverthrough the activity of multiple cytochrome P450(CYP)e nzymes,the majormetabolicisoformbeing the polymorphicallyexpressed CYP2C19 [5,6].Diazepami smetabolized byCYP2C19 and CYP3A. CYP2C19 isr esponsible foratleast half of the metabolismo fd iazepam [25][26][27][28][29].The majormetabolitei snordiazepam( desmethyldiazepam) withalong t 1/2 of 30 -200 h,whereasdiazepamh asab iphasict 1/2 of 20 -50h. The effectof the CYP2C19 polymorphismo nd iazepam clearance [30 -34]wasnots tudied in thiss tudybut maycontributep artlyt othe variability of derived data.…”