Evidence for Metabolic Activation of Omeprazole In Vitro and In Vivo

Abstract

Omeprazole (OPZ) is a proton pump inhibitor commonly used for the treatment of gastric acid hypersecretion. Studies have revealed that use of OPZ can induce hepatotoxicity, but the mechanisms by which it induces liver injury are unclear. This study aimed to identify reactive metabolites of OPZ, determine the pathways of the metabolic activation, and define the correlation of the bioactivation with OPZ cytotoxicity. Quinone imine-derived glutathione (GSH), N-acetylcysteine (NAC), and cysteine (Cys) conjugates were detected in OPZ-fortified rat and human liver microsomal incubations captured with GSH, NAC, or Cys. The same GSH conjugates were detected in bile of rats and cultured liver primary cells after exposure to OPZ. Similarly, the same NAC conjugates were detected in urine of OPZ-treated rats. The resulting quinone imine was found to react with Cys residues of hepatic protein. CYP3A4 dominated the metabolic activation of OPZ. Exposure to OPZ resulted in decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole attenuated the susceptibility of hepatocytes to the cytotoxicity of OPZ.

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database

“…We speculate that genetic polymorphisms of CYP2C19 likely constitute another contributing factor to adverse events in patients prescribed omeprazole alone, resulting in high exposure to its possible metabolic activation by other enzyme P450 3A4. 9) In our separate JADER analysis, rhabdomyolysis was also associated with omeprazole co-administration, even without concomitant statins or fibrates, indicating a large difference in time-to-onset days (17.5-196 d) for oral omeprazole treatment. 19) The high plasma/hepatic exposure to omeprazole in this genetically distinct population (Table 3) indicates that defective P450 2C19 activity could be a causal factor for adverse effects (Table 1, Fig.…”

“…8) Metabolic activation of omeprazole by P450 3A4 to a reactive quinone imine metabolite has been reported. 9) Modification of P450 2C19 expression by omeprazole was recently demonstrated 10) using stable and reproducibly generated human HepaSH cells obtained from engrafted livers in immunodeficient humanized-liver mice. 11) The purpose of the present study was to evaluate the virtual plasma/hepatic exposures to omeprazole in P450 2C19 poor metabolizer subjects (approx.…”

Suspected robenacoxib‐induced liver injury in a dog

“…Omeprazole, despite its potential hepatotoxic effects, 12 was considered less likely to have caused the liver injury directly due to previous repeated exposures to the drug (6 years, 3 years, 5 months and 4 months before presentation) without clinical signs reported. Nevertheless, the use of omeprazole alongside robenacoxib could have played a causative or contributing role in the development of the liver injury; the co‐administration of active substances that have a high degree of protein binding and robenacoxib could potentially increase the toxic effects of the latter (Onsior datasheet).…”

Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats

“…25 Similarly, diclofenac and omeprazole undergo similar metabolic activation process catalyzed by P450 enzymes, which is closely related to their cytotoxicity. 26,27 The present study aimed to explore the metabolic pathway of GRM in vitro and vivo, to identify the reactive metabolites of GRM, and to define the correlation between the metabolic activation and cytotoxicity of GRM.…”

“…For example, fungicide carbendazim is catalyzed by CYP1A2 to generate reactive quinone imine intermediates that covalently bind to cellular proteins, resulting in cytotoxicity . Similarly, diclofenac and omeprazole undergo similar metabolic activation process catalyzed by P450 enzymes, which is closely related to their cytotoxicity. , …”