Selectivity of omeprazole inhibition towards rat liver cytochromes P450

Abstract

1. The potency and selectivity of omeprazole as an inhibitor of cytochrome P450-mediated drug oxidations has been assessed in hepatic microsomes from the untreated, phenobarbitone-treated, beta-naphthoflavone-treated and dexamethasone-treated rat. Using the marker substrates diazepam, ethoxycoumarin, ethoxyresofurin and ethylmorphine in the above microsomal preparations, inhibitory activity against CYP1A, 2B, 2C and 3A members of the cytochrome P450 superfamily were determined. 2. In each situation studied the kinetics of inhibition by omeprazole were competitive in nature with Ki's ranging from 25 to > 1000 microM. Marker activities for the 3A family in microsomes from the dexamethasone-treated and phenobarbitone-treated rat (3-hydroxylation of diazepam and N-demethylation of ethylmorphine) were most susceptible to omeprazole inhibition (Km/Ki ratios greater than unity) compared with marker activities for the CYP1A, 2B and 2C sub-families (Km/Ki ratios < or = unity). 3. Omeprazole sulphoxide showed similar potency and selectivity of inhibition to its parent drug. Analogous studies with the same marker activities using ketoconazole indicated that both omeprazole and its sulphoxide metabolite are less potent as an inhibitor of cytochrome P4503A in rat than this well characterised prototype.

Cytoprotective potential of tiron and methyl palmitate against acetaminophen-induced acute liver injury

“…Tiron was reported to reduce bortezomib-induced cell death via a ROS-dependent mechanism (Ling et al 2003). Tiron also abolished H 2 O 2 production from melatonin-treated mitochondria (Zomorodi and Houston 1997). In addition, methyl palmitate significantly reduced the serum levels of IL-6 which was interestingly inconsistent with a previous study where the release of IL-6 was detected in kupffer cells and showed no detectable alteration in For personal use only.…”

Metabolism of melatonin by cytochrome P450s in rat liver mitochondria and microsomes

“…Thus, ketoconazole, which is a potent inhibitor of human CYP3A4, inhibited CYP3A1/2, CYP1A2‐ and CYP2C6‐mediated activities in rats [25]. Omeprazole, a selective inhibitor of human CYP2C19, has also been reported as a potent inhibitor of the CYP3A family in rat [26]. Quinidine, which is one of the most potent inhibitors of human CYP2D6, appears to be a relatively selective inhibitor for rat CYP2C6 and to have a weak inhibitory effect on members of CYP3A subfamily [25].…”

“…To define the CYPs responsible for the production of NAS and 6‐hydroxymelatonin, microsomes and mitochondria (mitoplasts) were incubated in the presence of CYP inhibitors: 5 μ m of quinidine (CYP2C6, CYP3A family), 10 μ m of sulfaphenazole (CYP2C6), 50 μ m of diethyldithiocarbamate (CYP2E1), 5 μ m of ketoconazole (CYP3A1/2, CYP1A2 and CYP2C6 inhibitor) and 20 μ m of furafylline (CYP1A2), 100 μ m omeprazole (CYP3A subfamily) [25, 26]. Inhibitors were screened for their effects on melatonin O‐demethylation and 6‐hydroxylation in mitochondria (mitoplasts) or microsomes at a melatonin concentration of 50 μ m .…”

Effects of omeprazole or cola beverage on the pharmacokinetics of oral DA‐8159, a new erectogenic, in rats

“…Hence, if the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of DA-8159 is changed by omeprazole or cola beverage, the mechanism could be different from itraconazole; not due to changes in absorption of DA-8159. This could be related to inhibition of hepatic microsomal cytochrome P450 (CYP) isozyme by omeprazole since the CYP3A1/2 catalyzed metabolism of DA-8159 in rats [8] and omeprazole is a competitive inhibitor of the CYP3A family based on in vitro rat hepatic microsomes [9]. The purpose of this study is to report the greater AUC of DA-8159 by omeprazole with respect to inhibition of CYP3A1/2 by omeprazole in rats.…”