Journal article
Identification and kinetics of microsomal and recombinant equine liver cytochrome P450 enzymes responsible for in vitro metabolism of omeprazole
Biochemical pharmacology, Vol.214, 115635
08/2023
PMID: 37285945
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Source: InCites
Abstract
In humans, omeprazole is metabolised by cytochrome P450 (CYP450) CYP2C19 and CYP3A4 with differences in CYP2C19 genotypes leading to variable response to therapy. Despite a wide use of omeprazole in horses with evidence of variable therapeutic efficiency, information regarding enzymatic metabolism is not currently available. This study aims to describe the in vitro kinetics of omeprazole metabolism and determine which enzyme(s) are responsible for omeprazole metabolism in horses. Omeprazole (0–800 uM) was incubated with liver microsomes and a panel of equine recombinant CYP450s (eq-rCYP). Metabolite concentrations were quantified by LC-MS and the kinetics of metabolites’ formation were calculated by non-linear regression analysis. The in vitro liver microsomes formed three metabolites (5-hydroxy-omeprazole, 5-O-desmethyl-omeprazole and omeprazole-sulfone). The 5-O-desmesthyl-omeprazole formation was best fitted to a two enzyme Michaelis-Menten (MM) model with the high affinity site Clint double that of the low affinity site. For 5-hydroxy-omeprazole the best fit was to a 1 enzyme MM model with a Clint higher than for 5-O-desmesthyl-omeprazole (0.12 vs 0.09 pmol/min/pmol P450). The formation of omeprazole-sulfone was negligible. Recombinant CYP3A89 and CYP3A97 produced substantial amounts of 5-hydroxy-omeprazole (1551.72 ng/mL and 1665.33 ng/mL, respectively), while 5-O-desmethyl-omeprazole and omeprazole-sulfone were formed to a much lesser extent by multiple eq-rCYP from the CYP2C and CYP3A family. In vitro metabolism of omeprazole in horses is different to that in humans, with major metabolites produced by the CYP3A family. The current study provides the basis for further investigations of CYP450 single nucleotide polymorphisms that could affect omeprazole metabolism and therapeutic efficacy.
Details
- Title
- Identification and kinetics of microsomal and recombinant equine liver cytochrome P450 enzymes responsible for in vitro metabolism of omeprazole
- Creators
- Gustavo Ferlini Agne - University of AdelaideAndrew A Somogyi - University of AdelaideBen Sykes - Massey UniversityHeather Knych - University of California, DavisBen Sykes - Massey UniversitySamantha Franklin - University of Adelaide
- Publication Details
- Biochemical pharmacology, Vol.214, 115635
- Publisher
- Elsevier Inc
- Identifiers
- 991013158711002368
- Copyright
- © 2023 Elsevier Inc. All rights reserved.
- Academic Unit
- Faculty of Science and Engineering
- Language
- English
- Resource Type
- Journal article