The interaction of omeprazole with rat liver cytochrome P450-mediated monooxygenase reactions in vitro and in vivo.
The effect of omeprazole on cytochrome P450-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 Ki for omeprazole was 40 +/- 27 microM with EM and 76 +/- 6 microM with ECOD in four separate rats. In preparations of rat hepatocytes the intrinsic clearance of diazepam was decreased substantially by 50 microM omeprazole (average inhibition 73%). In comparison 50 microM 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 P450 and ECOD activity. Thus omeprazole interacts with the mixed function oxidase system in vitro and in vivo.
Chenery
R J
RJ
Smith Kline & French Research Limited, The Frythe, Welwyn, Herts, U.K.
Ayrton
A
A
Oldham
H G
HG
Norman
S J
SJ
Standring
P
P
D015660:7-Alkoxycoumarin O-Dealkylase; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology; D005037:Ethylmorphine-N-Demethylase / Q000032:analysis; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009251:NADPH-Ferrihemoprotein Reductase; D009853:Omeprazole / Q000494:pharmacology*; D010088:Oxidoreductases / Q000032:analysis*; D010105:Oxygenases / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D002927:Cimetidine; D010088:Oxidoreductases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D005037:Ethylmorphine-N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D009853:Omeprazole; D003975:Diazepam