Metabolism and Pathways for Denitration of Organic Nitrates in the Human Liver

Abstract

Liver first-pass metabolism differs considerably among organic nitrates, but little information exists on the mechanism of denitration of these compounds in hepatic tissue. The metabolism of nitrooxybutyl-esters of flurbiprofen and ferulic-acid, a class of organic nitrates with potential therapeutic implication in variety of different conditions, was investigated in comparison with glyceryl trinitrate (GTN) in human liver by a multiple approach, using a spontaneous metabolism-independent nitric oxide (NO) donor [3-(aminopropyl)-1-hydroxy-3-isopropyl-2-oxo-1-triazene (NOC-5)] as a reference tool. Nitrooxybutyl-esters were rapidly and quantitatively metabolized to their respective parent compounds and the organic nitrate moiety nitrooxybutylalcohol (NOBA). Differently from GTN, which was rapidly and completely metabolized to nitrite, NOBA was slowly metabolized to nitrate. In contrast to the spontaneous NO donor NOC-5, NOBA and GTN did not generate detectable NO and failed to suppress the activity of cytochrome P450, an enzyme known to be inhibited by NO. The direct identification of NOBA after liver metabolism targets this compound as the functional organic nitrate metabolite of nitrooxybutyl-esters. Moreover, the investigation of the pathways for denitration of NOBA and GTN suggests that organic nitrates are not primarily metabolized to NO in the liver but to different extents of nitrite or nitrate depending in their different chemical structure. Therefore, cytochrome P450-dependent metabolism of concomitant drugs is not likely to be affected by oral coadministration of organic nitrates. However, the first pass may differently affect the pharmacological profile of organic nitrates in connection with the different extent of denitration and the distinct bioactive species generated and exported from the liver (nitrate or nitrite).

Nitrate-functionalized patch confers cardioprotection and improves heart repair after myocardial infarction via local nitric oxide delivery

“…Nitrate anion is the major hydrolysis product during early stage because of the relatively slow degradation of bulk PCL (Supplementary Fig 9 ). The released nitrate anion can further be metabolized to NO through the nitrate-nitrite-NO reduction pathway under the catalysis of various endogenous enzymes 29 , 30 . The conversion of nitrate and nitrite has been observed in PBS buffer with the addition of tissue homogenates from the hearts, which confirmed the presence of relevant reductases (Fig.…”

“…Organic nitrates represent a conventional class of NO-donating agents that have been used to treat CVDs (ischemic heart disease, heart failure, and hypertension) for many years 4 . After uptake, organic nitrates first experienced denitration and were metabolized to nitrate (NO 3 − ) or nitrite (NO 2 − ) depending on the structure of them 29 . The bioactivation is mediated by either non-enzymatic (endogenous reductants) or enzymatic reactions.…”

Increasing dietary nitrate has no effect on cancellous bone loss or fecal microbiome in ovariectomized rats

“…Biotransformation of organic nitrates is not fully understood and can vary widely with the class of organic nitrate 59. Organic nitrates typically undergo liver first‐pass metabolism; however, the exact mechanism of denitration (release of NO) in the vasculature or different tissue sites remains a matter of debate 60, 61. Organic nitrates have potent acute effects, while the metabolic conversion of inorganic nitrate to nitric oxide is more efficient under hypoxic and acidic conditions that may not have been reproduced under these study conditions 57.…”

Methods to Reduce Liver Ischemia/Reperfusion Injury

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