Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole

Martı́nez, Carmen; Andreu, Inmaculada; Amo, Gemma; Miranda, Miguel A.; Esguevillas, Gara; Torres, Marı́a José; Blanca‐López, Natalia; Blanca, Miguel; García‐Martín, Elena; Agúndez, José A. G.

doi:10.1016/j.bcp.2014.09.005

Cited by 25 publications

(22 citation statements)

References 45 publications

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“…Another factor to consider that may contribute to the low sensitivity of diagnostic tests is the incomplete characterization of the chemical structures of metamizole and its metabolites [30]. Four major metamizole metabolites have been described in the literature [31]; however, we recently demonstrated the presence of arachidonoyl metabolites in patients receiving metamizole [32], and additional metabolites, such as oxalic acid derivatives, have been reported elsewhere [33]. It cannot be ruled out that in some patients metamizole metabolites may contribute to hypersensitivity reactions.…”

Section: Discussionmentioning

confidence: 99%

Allergic Reactions to Metamizole: Immediate and Delayed Responses

Blanca‐López

Pérez‐Sánchez²,

Agúndez³

et al. 2016

Int Arch Allergy Immunol

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Background: Pyrazolones are the most common causes of selective nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We studied a large group of patients with immediate and delayed selective responses to metamizole. Methods: Patients with suspicion of hypersensitivity to metamizole were evaluated. We verified acetylsalicylic acid tolerance and classified patients as immediate or delayed responders if they showed symptoms less or more than 24 h after metamizole administration. Skin tests were performed and if negative, a basophil activation test (BAT) was performed on immediate responders. If it was negative, we performed a drug provocation test (DPT) with metamizole. Results: A total of 137 patients were included: 132 reacted within 24 h (single NSAID-induced urticaria/angioedema/anaphylaxis; SNIUAA) and 5 after 24 h (single NSAID-induced delayed hypersensitivity reaction; SNIDHR). Most SNIUAA patients developed anaphylaxis (60.60%); for SNIDHR, maculopapular exanthema was the most frequent entity (60%). Skin testing was positive in 62.04% of all cases and BAT in 28% of the SNIUAA patients with negative skin tests. In 5.1% of the cases, DPT with metamizole was needed to establish the diagnosis. In 22.62% of the cases, diagnosis was established by consistent and unequivocal history of repeated allergic episodes in spite of a negative skin test and BAT. Conclusions: SNIUAA to metamizole is the most frequent type of selective NSAID hypersensitivity, with anaphylaxis being the most common clinical entity. It may occur within 1 h after drug intake. SNIDHR occurs in a very low percentage of cases. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of metamizole and its metabolites.

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Section: Discussionmentioning

confidence: 99%

Allergic Reactions to Metamizole: Immediate and Delayed Responses

Blanca‐López

Pérez‐Sánchez²,

Agúndez³

et al. 2016

Int Arch Allergy Immunol

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“…Consistently, another experimental study performed over 10 years ago analyzing liver microsomes of patients treated with metamizole revealed not just a selectively higher expression of CYP3A4 (2.8‐fold), but also of CYP2B6 (3.8‐fold) in comparison to untreated individuals . As a consequence, it has to be hypothesized that metamizole could interact with other substances metabolized via these CYP systems, including frequently applied agents such as aspirin or immunosuppressants such as tacrolimus . For instance, a small trial in patients on long‐term cyclosporin (CsA) treatment after heart or kidney transplantation could indeed show an association between short‐course administration of metamizole and a mild decrease in CsA plasma concentrations, especially in the first hours after metamizole intake.…”

Section: Hepatic Metabolism Of Metamizolementioning

confidence: 83%

“…66 As a consequence, it has to be hypothesized that metamizole could interact with other substances metabolized via these CYP systems, including frequently applied agents such as aspirin or immunosuppressants such as tacrolimus. [67][68][69][70][71] For instance, a small trial in patients on long-term cyclosporin (CsA) treatment after heart or kidney transplantation could indeed show an association between short-course administration of metamizole and a mild decrease in CsA plasma concentrations, especially in the first hours after metamizole intake. However, no dose adjustment of CsA was necessary in this small cohort of patients.…”

Section: Hepatic Metabolism Of Metamizolementioning

confidence: 99%

Metamizole (Dipyrone) and the Liver: A Review of the Literature

Lutz

2019

The Journal of Clinical Pharma

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Metamizole, also known as dipyrone, was introduced to the market nearly a century ago. Due to its excellent analgesic, antipyretic, and spasmolytic properties combined with its mostly favorable gastrointestinal tolerability, the drug was extensively applied worldwide during the first decades after its market introduction. Although rare, agranulocytosis is a well‐known adverse event of metamizole and led to its withdrawal from the market in a number of countries beginning in the 1960s. Nevertheless, metamizole is still a frequently used drug worldwide either legally (by prescription in some countries, over the counter in other countries) or without official approval (especially by immigrants knowing the drug from their home countries) or even illegally (due to its growing application as an adulterant in illicit drugs). Metamizole undergoes extensive metabolism in the liver and cases of potential metamizole‐associated hepatotoxicity have been described. Here, the literature is extensively reviewed for the first time regarding hepatic effects associated with the use of metamizole.

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“…All mentioned SNPs cause a major decrease on enzyme activity both, in vitro and in vivo [13,14], and are associated with slow acetylation of drugs and xenobiotics [14,15] and with adverse drug reactions [16][17][18][19][20]. NAT2 genotypes are characterized as slow, intermediate, or rapid acetylators.…”

Section: Introductionmentioning

confidence: 99%

“…Heterogeneity among slow acetylators occur, because of genotypes leading to very slow acetylation phenotypes [15]. The determination of the defect NAT2 SNPs mentioned above permits an accurate prediction of the acetylation phenotype with a relatively short number of SNP analyses [21].…”

Section: Introductionmentioning

confidence: 99%

NAT2 polymorphisms and risk for Parkinson’s disease: a systematic review and meta-analysis

Jiménez‐Jiménez

Alonso‐Navarro

García‐Martín

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Despite several recent meta-analyses showing an association between several polymorphisms in genes related with detoxification mechanisms such as cytochrome P4502D6 (CYP2D6), and glutathione transferases M1 and T1 (GSTM1, and GSTT1), data on NAT2 gene polymorphisms obtained from the current meta-analysis do not support a major association with PD risk, except in Asian populations. However, data from many studies are incomplete and therefore insufficient data exists to draw definitive conclusions. Several studies suggesting gene-gene and gene-environmental factors involving NAT2 gene in PD risk await confirmation.

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Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole

Cited by 25 publications

References 45 publications

Allergic Reactions to Metamizole: Immediate and Delayed Responses

Allergic Reactions to Metamizole: Immediate and Delayed Responses

Metamizole (Dipyrone) and the Liver: A Review of the Literature

NAT2 polymorphisms and risk for Parkinson’s disease: a systematic review and meta-analysis

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