Abstract

Oxidative metabolism of omeprazole (OPZ) was studied in 14 human liver microsomes in relation to the 4'-hydroxylation capacity of S-mephenytoin. The formation of 5-hydroxyomeprazole and omeprazole sulfone (OPZ-SFN) from OPZ exhibited a biphasic kinetic behavior, indicating that at least two distinct enzymes are involved in either of the metabolic pathways of OPZ. By using a two-enzyme kinetic approach, the activities were described by high (Km1 and Vmax1)- and low-affinity components (Km2 and Vmax2). The respective mean (+/- S.D.) kinetic parameters for 5-hydroxylation and sulfoxidation were: Km1 = 6.0 +/- 2.4 and 10.2 +/- 7.2 microM and Vmax1 = 88.0 +/- 70.2 and 66.9 +/- 53.9 pmol/mg/min; Km2 = 106 +/- 127 and 482 +/- 472 microM and Vmax2 = 116 +/- 88 and 299 +/- 131 pmol/mg/min. Among these kinetic parameters, only the Vmax1 of 5-hydroxylation gave a close correlation with the corresponding parameter of S-mephenytoin (rs = 0.911, P < .01). In addition, OPZ and S-mephenytoin inhibited competitively each other's metabolism with the respective Ki values of 2.0 and 162 microM. Interestingly, OPZ-SFN also inhibited competitively 4'-hydroxylation of S-mephenytoin with a Ki value of 8.2 microM. Moreover, polyclonal antibodies raised against S-mephenytoin 4'-hydroxylase (P450 form) partially inhibited the 5-hydroxylation of OPZ, whereas no inhibition was observed for the sulfoxidation. These findings suggest that S-mephenytoin 4'-hydroxylase is an enzyme primarily responsible for the 5-hydroxylation of OPZ and further metabolism of OPZ-SFN, but not for the sulfoxidation of OPZ in human liver microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)