Acute liver injury related to the use of niperotidine

Gasbarrini, Giovanni; Gentiloni, N; Febbraro, Stefania; Gasbarrini, Antonio; Campli, C. Di; Cesana, Marina; Miglio, F; Miglioli, M.; Ghinelli, F; D'Ambrosi, A; Amoroso, P; Pacini, F.; Salvadori, G

doi:10.1016/s0168-8278(97)80365-0

Cited by 12 publications

(6 citation statements)

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“…The MDP carbenes form a metabolic-intermediate complex (MIC) with the heme-iron via coordination, leading to quasi-irreversible inhibition of CYP450 (Figure ). − Inhibition of cytochromes arising due to the reactive metabolite (RM) generated by the biotransformation of the substrate itself is known as the mechanism-based inhibition (MBI) of cytochromes. − The reactive species or RM is termed as the mechanism-based inhibitor which binds within the active site and interferes with the catalytic cycle of CYP450. MBI results in a more profound and prolonged effect as compared to reversible inhibitors, thus underlying its concern in drug metabolism. ,− …”

Section: Introductionmentioning

confidence: 99%

“…The MDP moiety forms an important constituent of several drugs, pesticides, flavoring agents, and naturally occurring compounds (Figure ). − Drugs containing the MDP moiety which are reported to form the reactive carbene intermediate and MIC with heme-iron include tadalafil and paroxetine. Tadalafil, a selective phosphodiesterase-5 (PDE-5) inhibitor, has been reported to inhibit the activity of CYP3A4, via the formation of MIC between carbene intermediate and heme-iron .…”

Section: Introductionmentioning

confidence: 99%

“…Paroxetine, a selective serotonin reuptake inhibitor, acts as the potent inhibitor of CYP2D6 by forming an MIC of carbene-Fe . Niperotidine is another example of a drug containing MDP moiety, which was withdrawn from the market owing to acute hepatitis . The reactive metabolites via the oxidation of MDP unit have been implicated behind this toxicity; however, no confirmatory reports are available in this regard.…”

Section: Introductionmentioning

confidence: 99%

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Carbene Generation by Cytochromes and Electronic Structure of Heme-Iron-Porphyrin-Carbene Complex: A Quantum Chemical Study

2013

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Carbene-heme-iron-porphyrin complexes generated from cytochrome P450 (CYP450)-mediated metabolism of compounds containing methylenedioxyphenyl (MDP) moiety lead to the mechanism-based inhibition (MBI) of CYPs. This coordination complex is termed as the metabolic-intermediate complex (MIC). The bioinorganic chemistry of MDP carbenes has been studied using quantum chemical methods employing density functional theory (B3LYP functional with implicit solvent corrections) to (i) analyze the characteristics of MDP-carbene in terms of singlet-triplet energy difference, protonation, and dimerization energies, etc.; (ii) determine the electronic structure and analyze the Fe-carbene interactions; and (iii) elucidate the potential reaction pathways for the generation of carbene, using Cpd I (iron(IV)-oxo-porphine with SH(-) as the axial ligand) as the model oxidant to mimic the activity of CYP450. The results show that MDP-carbenes are sufficiently stable and nucleophilic, leading to the formation of stable MIC (-40.35 kcal/mol) on the doublet spin state, formed via interaction between σ(LP) of carbene and empty dz(2) orbital of heme-iron. This was aided by the back-bonding between filled d(xz) orbital of heme-iron and the empty p orbital of carbene. The mechanistic pathway proposed in the literature for the generation of MDP-carbene (CH hydroxylation followed by water elimination) was studied, and observed to be unfavorable, owing to the formation of highly stable hydroxylated product (-57.12 kcal/mol). An intriguing pathway involving hydride ion abstraction and proton transfer followed by water elimination step was observed to be the most probable pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Carbene Generation by Cytochromes and Electronic Structure of Heme-Iron-Porphyrin-Carbene Complex: A Quantum Chemical Study

2013

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“…1) and niperotidine (3) (H 2 -receptor antagonists), introduced for the treatment of acid reux, heartburn, ulcers and Zollinger-Ellison syndrome. 3,4 Various neonicotinoids containing nitroenamine moieties are used as insecticidal agents. Nitenpyram (4) and nithiazine (5) are the rst generation neonicotinoids.…”

Section: Introductionmentioning

confidence: 99%

Nitro ⇌ aci-nitro tautomerism and E/Z isomeric preferences of nitroethenediamine derivatives: a quantum chemical study

Dhaked

Bharatam

2013

RSC Adv.

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“…In the past, two H2 receptor antagonists have been withdrawn because of high risk of liver toxicity [4,5]. However liver toxicity has never been shown to be a class effect of H2 receptor antagonists [6].…”

Section: Introductionmentioning

confidence: 99%

Hepatitis following famotidine: a case report

2009

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H2 receptor antagonists can rarely cause idiosyncratic drug reactions leading to acute hepatitis. Famotidine, however, is considered a relatively safe drug with regards to hepatotoxicity. We report a case of a 47 year old male with a history of hepatitis C who developed acute hepatitis on the third day of hospitalization with a dramatic rise in his liver enzymes from normal values at the time of admission. The acute rise in liver enzymes made us consider an adverse drug reaction and famotidine was discontinued. Subsequently his liver enzymes came back to normal in seven days. Thus, physicians should consider famotidine induced hepatitis as a possible etiology of acute liver dysfunction.

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Acute liver injury related to the use of niperotidine

Cited by 12 publications

References 6 publications

Carbene Generation by Cytochromes and Electronic Structure of Heme-Iron-Porphyrin-Carbene Complex: A Quantum Chemical Study

Carbene Generation by Cytochromes and Electronic Structure of Heme-Iron-Porphyrin-Carbene Complex: A Quantum Chemical Study

Nitro ⇌ aci-nitro tautomerism and E/Z isomeric preferences of nitroethenediamine derivatives: a quantum chemical study

Hepatitis following famotidine: a case report

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