The interaction of omeprazole with rat liver cytochrome P450-mediated monooxygenase reactions in vitro and in vivo

Abstract The effect of omeprazole on cytochrome P 450 -mediated monooxygenase reactions was assessed in rat liver S9 utilising ethylmorphine- N -demethylase (EM) and ethoxycoumarin- O -deethylase (ECOD) activities. The inhibition of EM by omeprazole was judged to be predominantly reversible in mechanism. The average K i for omeprazole was 40 ± 27 μ M with EM and 76 ± 6 μ M with ECOD in four separate rats. In preparations of rat hepatocytes the intrinsic clearance of diazepam was decreased substantially by 50 μM omeprazole (average inhibition 73%). In comparison 50 μM cimetidine inhibited the intrinsic clearance of diazepam by 50%. The relationship between these two in vitro models for drug interactions is discussed in the context of previously published drug inhibition data. Moreover, repeated administration of omeprazole to adult male rats (500 mg·kg −1 , 14 days, p.o.) resulted in statistical increases in liver weight, cytochrome P 450 and ECOD activity. Thus omeprazole interacts with the mixed function oxidase system in vitro and in vivo .