Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

Gastal, Gabriela Roncone; Moreira, Simone da Nóbrega Tomaz; Noble, Caroline Furtado; Ferreira, Leslie Ecker; França, Paulo Henrique Condeixa de; Pinho, Mauro

doi:10.1590/s0004-28032012000200007

Cited by 9 publications

(6 citation statements)

References 15 publications

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“…The combined frequency of alleles TPMT*2, *3A, *3B and *3C in the overall REFARGEN cohort is 4.5%, with similar distribution in self‐reported white, brown and black individuals (Table ). These data are consistent with those of previously published studies in Brazilian healthy subjects and in children with acute lymphoblastic leukaemia . No frequency data were found for TPMT*4 in Brazilians.…”

Section: Resultssupporting

confidence: 91%

Pharmacogenomics research and clinical implementation in Brazil

Rodrigues‐Soares

Suarez‐Kurtz

2019

Basic Clin Pharma Tox

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We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.

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Section: Resultssupporting

confidence: 91%

Pharmacogenomics research and clinical implementation in Brazil

Rodrigues‐Soares

Suarez‐Kurtz

2019

Basic Clin Pharma Tox

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“…Many studies have shown that hepatotoxicity seems to be related to the accumulation of methylated metabolites such as 6-MMP [2, 8]. The enzyme TPMT is the key enzyme in the metabolic pathway: patients with very high TPMT activity are resistant to thiopurine drugs due to shunting of 6-MP away from 6 TGN towards over production of 6-MMP [8, 9], and at the risk of hepatotoxicity due to high 6-MMP concentrations[10]. …”

Section: Discussionmentioning

confidence: 99%

Suspected azathioprine induced liver cirrhosis: an unusual side effect

Trabelsi¹,

Hamami²,

Souguir³

et al. 2014

Pan Afr Med J

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In recent years, the hepatotoxic potential of thiopurines, in particular 6-thioguanine (6-TG) has been discussed in literature. However, cirrhosis was exceptionally reported. We report the case of a 56-year-old woman with ileocaecal Crohn's disease treated with azathioprine. After taking azathioprine (2 mg/kg daily) for four years, she underwent surgical treatment for acute intestinal obstruction. In peroperative, we noticed a cirrhotic liver. A surgical biopsy was performed and the diagnosis of cirrhosis was confirmed. Autoimmune and viral liver diseases were ruled out by laboratory parameters. Therefore, Azathioprine is believed to be the causative actor for inducing liver cirrhosis. Thus, treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle.

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“…Many studies have shown that hepatotoxicity seems to be related to the accumulation of methylated metabolites such as 6-MMP [3,9]. The enzyme TPMT is the key enzyme in the metabolic pathway: patients with very high TPMT activity are resistant to thiopurine drugs due to shunting of 6-MP away from 6 TGN towards over production of 6-MMP [9,10], and at the risk of hepatotoxicity due to high 6-MMP concentrations [11][12][13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

Azathioprine induced liver cirrhosis: An unusual side effect

Trabelsi¹,

Hamami²,

Ksiaa³

et al. 2013

OJGas

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In recent years, the hepatotoxic potential of thiopurines, in particular 6-thioguanine (6-TG), has been discussed in literature. However, cirrhosis was exceptionally reported. We report the case of a 56-year-old woman with ileocaecal Crohn's disease treated with azathioprine. After taking azathioprine (2 mg/kg daily) for four years, she underwent surgical treatment for acute intestinal obstruction. In peroperative, we noticed a cirrhotic liver. A surgical biopsy was performed and the diagnosis of cirrhosis was confirmed. Autoimmune and viral liver diseases were ruled out by laboratory parameters. Therefore, Azathioprine is believed to be the causative factor for inducing liver cirrhosis. Thus, treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle.

show abstract

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

Cited by 9 publications

References 15 publications

Pharmacogenomics research and clinical implementation in Brazil

Pharmacogenomics research and clinical implementation in Brazil

Suspected azathioprine induced liver cirrhosis: an unusual side effect

Azathioprine induced liver cirrhosis: An unusual side effect

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