The potential role of pharmacogenomics and biotransformation in hypersensitivity reactions to paracetamol

Agúndez, José A. G.; Gómez-Tabales, Javier; Pérez, Francisco Javier Ruano; García‐Martín, Elena

doi:10.1097/aci.0000000000000452

Cited by 8 publications

(7 citation statements)

References 74 publications

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“…The first metabolic pathways include glucuronidation by several UGT enzymes, and among these, the most relevant is UGT1A6 [ 18 ]. Acetaminophen glucuronides account for more than 50% of the urine metabolites [ 4 ]. Unlike NSAIDs, acetaminophen causes frequent dose-dependent toxicity [ 25 ], and it is plausible that, if genetic variations related to impaired acetaminophen biodisposition could be identified, impaired acetaminophen metabolism could be a relevant pharmacogenomics target.…”

Section: Discussionmentioning

confidence: 99%

“…Acetaminophen is widely used for the treatment of fever and pain [ 2 ], and it causes fewer cardiovascular, gastric, and renal adverse events than NSAIDs [ 3 ]. However, it shares with NSAIDs their antipyretic and analgesic properties as well as adverse drug events, such as hypersensitivity events in their two main clinical forms (selective hypersensitivity and cross-hypersensitivity) [ 4 , 5 , 6 , 7 ]. In addition, acetaminophen causes idiosyncratic drug-induced liver injury (iDILI) [ 8 , 9 , 10 ], as NSAIDs do, and it has been hypothesized that functional genetic variations in the COX-enzymes are related to iDILI risk and cross-hypersensitivity to COX-inhibitors [ 11 , 12 , 13 , 14 , 15 ], thus suggesting that patients with impaired COX activity are more prone to developing adverse drug events when using COX inhibitors [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…The pathogenesis of high-dose-related acetaminophen liver failure involves the formation of the highly reactive N-acetyl-p-benzoquinone imine (NAPQI) metabolite, a product of cytochrome P450 enzymes that causes glutathione depletion and that binds covalently to proteins [ 16 ]. It has been postulated also that NAPQI could be related to selective hypersensitivity to acetaminophen [ 4 ]. Therefore, the relevance of acetaminophen metabolism is linked both to the generation of reactive metabolites and interindividual variability in acetaminophen biodisposition.…”

Section: Introductionmentioning

confidence: 99%

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Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man

Cerezo-Arias

Gómez-Tabales

Martí

et al. 2022

JPM

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Acetaminophen (paracetamol) is a widely used drug that causes adverse drug events that are often dose-dependent and related to plasma drug concentrations. Acetaminophen metabolism strongly depends on UGT1A enzymes. We aimed to investigate putative factors influencing acetaminophen pharmacokinetics. We analyzed acetaminophen pharmacokinetics after intravenous administration in 186 individuals, and we determined the effect of sex; body mass index (BMI); previous and concomitant therapy with UGT1A substrates, inhibitors, and inducers; as well as common variations in the genes coding for UGT1A1, UGT1A6, and UGT1A9. We identified sex and UGT1A6 genetic variants as major factors influencing acetaminophen pharmacokinetics, with women showing lower clearance (p < 0.001) and higher area under the plasma drug concentration-time curve (AUC) values than men (p < 0.001). UGT1A6 genetic variants were related to decreased acetaminophen biodisposition. Individuals who were homozygous or double-heterozygous for variant UGT1A6 alleles showed a 22.5% increase in t1/2 values and a 22.8 increase in drug exposure (p < 0.001, and 0.006, respectively) after correction by sex. The effect is related to the UGT1A6*2 and UGT1A6*4 variant alleles, whereas no effect of UGT1A6*3 and UGT1A9*3 alleles, BMI, or drug–drug interaction was identified in this study. We conclude that sex and UGT1A6 variants determine acetaminophen pharmacokinetics, thus providing evidence to eventually developing pharmacogenomics procedures and recommendations for acetaminophen use.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man

Cerezo-Arias

Gómez-Tabales

Martí

et al. 2022

JPM

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“…There are seven classes within cytosolic GSTs (GSTA, GSTM, GSTP, GSTT, GSTO, GSTZ, and GSTS) that differ in their chemical, physical, and structural properties [50]. The effect of polymorphisms in the genes encoding these cytosolic enzymes, as well as that of gene duplications and deletions, has been extensively studied and their functional relevance in the context of drug detoxication has been highlighted [25,[76][77][78][79]. Here, we will focus on their impact on DHRs development.…”

Section: Glutathione Transferasesmentioning

confidence: 99%

Variability of the Genes Involved in the Cellular Redox Status and Their Implication in Drug Hypersensitivity Reactions

2021

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Adverse drug reactions are a major cause of morbidity and mortality. Of the great diversity of drugs involved in adverse drug reactions, the most frequent are non-steroidal anti-inflammatory drugs followed by -lactam antibiotics. The redox status regulates the level of reactive oxygen and nitrogen species (RONS). RONS interplay and modulate the action of diverse biomolecules, such as inflammatory mediators and drugs. In this review, we address the role of the redox status in the initiation, as well as in the resolution of inflammatory processes involved in drug hypersensitivity reactions. We summarize the association findings between drug hypersensitivity reactions and variants in the genes that encode the enzymes related to the redox system such as enzymes related to glutathione: Glutathione S-transferase (GSTM1, GSTP, GSTT1) and glutathione peroxidase (GPX1), thioredoxin reductase (TXNRD1 and TXNRD2), superoxide dismutase (SOD1, SOD2, and SOD3), catalase (CAT), aldo-keto reductase (AKR), and the peroxiredoxin system (PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, PRDX6). Based on current evidence, the most relevant candidate redox genes related to adverse drug reactions are GSTM1, TXNRD1, SOD1, and SOD2. Increasing the understanding of pharmacogenetics in drug hypersensitivity reactions will contribute to the development of early diagnostic or prognosis tools, and will help to diminish the occurrence and/or the severity of these reactions.

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“…Interindividual variability in drug metabolism is likely to be involved in HDRs ( Agúndez et al, 2015a , Agúndez et al, 2018 ; García-Martín et al, 2015 ; Ariza et al, 2016 ; Sánchez-Gómez et al, 2016 ; Plaza-Serón et al, 2018 ). A substantial part of such interindividual variability is associated with polymorphisms in genes coding drug-metabolizing enzymes.…”

Section: Introductionmentioning

confidence: 99%

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs

Macías¹,

García-Menaya

Martí³

et al. 2021

Front. Pharmacol.

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Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.

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The potential role of pharmacogenomics and biotransformation in hypersensitivity reactions to paracetamol

Cited by 8 publications

References 74 publications

Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man

Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man

Variability of the Genes Involved in the Cellular Redox Status and Their Implication in Drug Hypersensitivity Reactions

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs

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