Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

Abstract

Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100 mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3 mg/kg/day, p.o.) and OME (100 mg/kg/day, p.o., 7 days) + TPPU (3 mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE2 was monitored. While OME treatment by itself exhibited variable effects on PGE2 induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME + TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study.

Pharmacological inhibition of soluble epoxide hydrolase or genetic deletion reduces diclofenac-induced gastric ulcers

“…Helander et al demonstrated that 16 h after radioactive omeprazole administration, the radioactivity of the stomach was 100 times higher than blood [48]. The concentration of TPPU in plasma was similar to the previously published literature [4]. Like TPPU, omeprazole appears to show excellent target occupancy.…”

“…Diclofenac is known to be metabolized by uridine 5′-diphosphoglucuronosyl transferase 2B7, cytochrome P450s (CYP) 2C9 and 3A4 [44]. Omeprazole is known to increase activity of CYP3A4 [4]. We measured the concentration of DCF and omeprazole to evaluate if omeprazole treatment increased the metabolism of DCF.…”

“…Over 30 million people use NSAIDs daily [3], making gastrointestinal toxicity a major health issue. Though many drugs are available to alleviate NSAID-induced ulceration, inhibitors of soluble epoxide hydrolase (sEH), which decrease pain [4] and inflammation [5] hold promise to decrease such ulcers [1, 6]. …”

Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

“…3). This increase in epoxide-containing lipids may result from increased biosynthesis by induced P450 enzymes (Goswami et al, 2015), whereas the increase caused by TPPU is from reduced metabolism. Levels of other quantified metabolites were not altered significantly and are presented in Supplemental Table 1.…”

“…An anti-inflammatory role of omeprazole in decreasing ulcer has been reported (Biswas et al, 2003). The reduction of ulcers by OME is attributable, at least in part, to induction of key P450 oxidases, thus increasing the biosynthesis of anti-inflammatory epoxy fatty acids (Goswami et al, 2015). Thus, the efficacy of TPPU, which stabilizes epoxy fatty acids, on prevention of NSAID-induced ulcers is not surprising.…”