[Enzyme kinetic studies on the in vitro metabolism of omeprazole by Chinese human liver microsomes].
In the present study, a specific and reliable method was developed for the determination of omeprazole and its two major metabolites, hydroxyomeprazole (OH-OPZ) and omeprazole sulfone (OPZ-SFN) in Chinese adult human liver microsome by reversed phase HPLC assay. Formation of these metabolites is linear for at least 60 min and between 0.25 and 1 mg.ml-1 of microsomal protein. The enzyme kinetic analysis of the reaction revealed that the hydroxylation Vmax and K(m) obtained with the human liver microsomal preparation were 42.9 nmol.min-1.(mg protein)-1 and 6.49 mumol.L-1, respectively. The maximum formation rates of OPZ-SFN (Vmax) was 6.63 nmol.min-1.(mg protein)-1, with a K(m) value of 11.8 mumol.L-1. A number of compounds were tested for their ability to inhibit OPZ metabolism. Our results showed that mephenytoin, diazepam and nordiazepam are competitive inhibitors and papaverine is an uncompetitive inhibitor of OPZ hydroxylation. These studies suggest that the same isozyme metabolising MP, DZ and NDZ (may be P450 2C or P450 3A) may be involved in the hydroxylation of OPZ. Moreover, the compounds tested also have some effects on the formation of OPZ-SFN in vitro with Chinese human liver microsomes.
Zhao
L
L
Department of Pharmacology, Beijing Medical University.
Lou
Y Q
YQ
D000328:Adult; D000897:Anti-Ulcer Agents / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D066298:In Vitro Techniques; D008617:Mephenytoin / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D009853:Omeprazole / Q000378:metabolism*; D010208:Papaverine / Q000494:pharmacology
D000897:Anti-Ulcer Agents; D010208:Papaverine; D009853:Omeprazole; D008617:Mephenytoin