Acute Liver Failure in a Patient Treated With Metamizole

Krisai, Philipp; Rudin, Deborah; Grünig, David; Scherer, Kathrin; Pichler, Werner J.; Terracciano, Luigi; Krähenbühl, Stephan

doi:10.3389/fphar.2019.00996

Cited by 15 publications

(17 citation statements)

References 26 publications

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“…Even if the interaction with CYP1A2 and CYP2C19 inhibitors is quantitatively small, this does not mean that this interaction is clinically negligible. Important adverse reactions of metamizole are hypotensive reactions, skin eruptions, myelotoxicity possibly leading to agranulocytosis and hepatic injury [33]. While hepatic injuries and skin toxicities are mainly dose-independent, immunological reactions [33,34], hypotensive reactions and myelotoxicity appear to be dose-dependent.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Bachmann

Duthaler

Meyerzuschwabidissen

et al. 2021

Preprint

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Aim: Metamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite is 4-methylaminoantipyrine (4-MAA), which can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P450 (CYP)-dependent reactions. Our aim was to identify the CYPs involved. Methods: We investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in healthy volunteers. Results: The experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation. CYP2C19 and CYP2D6 contributed to N-demethylation but not to FAA formation. In the subsequent clinical study, we investigated the influence of ciprofloxacin (strong CYP1A2 inhibitor), fluconazole (strong CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of a single dose of metamizole in n=12 healthy volunteers in a randomized, placebo-controlled, double-blind study. Both ciprofloxacin and fluconazole inhibited the metabolism of 4-MAA, confirming the in vitro results. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the AUC0-12h of 4-MAA by 51%, 17% and 92%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole decreased the AUC0-12h of 4-AA by 27%, 12% and 24%, respectively, and of 4-FAA by 33%, 9% and 51%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the half-life of 4-MAA from 3.22 h (placebo) to 3.91, 3.69 and 6.07 h, respectively. Conclusion: CYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. CYP1A2 inhibition increases the 4-MAA exposure by a factor of approximately 1.5, which could be relevant for dose-dependent adverse reactions.

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Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Bachmann

Duthaler

Meyerzuschwabidissen

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…In many countries, including Germany, metamizole is inexpensive, widely available and therefore often used in animal research and veterinary medicine. It has a low risk of causing acute liver failure and has been shown to have no toxic effects on hepatocytes [ 33 , 34 ]. Agranulocytosis, which is a known severe adverse effect of metamizole treatment, has led to its ban in several countries.…”

Section: Discussionmentioning

confidence: 99%

Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation

et al. 2020

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Background Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP). Methods Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion. Results Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend.

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“…A limit of the method that test as performed unblinded. This method has not be compared to RUCAM a part for a single case (Krisai et al, 2019).…”

Section: Monocyte Derived Hepatocyte Likementioning

confidence: 99%

Drug-Induced Liver Injury: Biomarkers, Requirements, Candidates, and Validation

Meunier

Larrey

2019

Front. Pharmacol.

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The hepatotoxicity of drugs is the main cause of drug withdrawal from the pharmaceutical market and interruption of the development of new molecules. Biomarkers are useful in several situations. In case of suspected drug-induced liver injury (DILI), biomarkers can be used to confirm liver damage, its severity, prognosis, confirm drug causality, or define the type of DILI. In this review, we will first present the currently used biomarkers and candidate biomarkers for the future. The current biomarkers are certainly very helpful including with the assistance of diagnostic method such the Roussel Uclaf Causality Assessment Method, but provide a limited information for the early detection of liver injury, the role of specific drug and the prediction of DILI. Some biomarkers are promising but they are not yet available for routine use. Studies are still needed to confirm their interest, particularly in comparison to Roussel Uclaf Causality Assessment Method.

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Acute Liver Failure in a Patient Treated With Metamizole

Cited by 15 publications

References 26 publications

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Cytochrome P450 1A2 is the most important enzyme for hepatic metabolism of the metamizole metabolite 4-methylaminoantipyrine

Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation

Drug-Induced Liver Injury: Biomarkers, Requirements, Candidates, and Validation

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