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Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleoti...

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Autores principales: Lucafò, Marianna, Stocco, Gabriele, Martelossi, Stefano, Favretto, Diego, Franca, Raffaella, Malusà, Noelia, Lora, Angela, Bramuzzo, Matteo, Naviglio, Samuele, Cecchin, Erika, Toffoli, Giuseppe, Ventura, Alessandro, Decorti, Giuliana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523194/
https://www.ncbi.nlm.nih.gov/pubmed/30987408
http://dx.doi.org/10.3390/genes10040277
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author Lucafò, Marianna
Stocco, Gabriele
Martelossi, Stefano
Favretto, Diego
Franca, Raffaella
Malusà, Noelia
Lora, Angela
Bramuzzo, Matteo
Naviglio, Samuele
Cecchin, Erika
Toffoli, Giuseppe
Ventura, Alessandro
Decorti, Giuliana
author_facet Lucafò, Marianna
Stocco, Gabriele
Martelossi, Stefano
Favretto, Diego
Franca, Raffaella
Malusà, Noelia
Lora, Angela
Bramuzzo, Matteo
Naviglio, Samuele
Cecchin, Erika
Toffoli, Giuseppe
Ventura, Alessandro
Decorti, Giuliana
author_sort Lucafò, Marianna
collection PubMed
description The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn’s disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio (LME p = 0.041) and 30% decrease in clinical efficacy (LME p = 0.0031). GSTA1 variant (12.8% of patients) showed a trend (p = 0.046, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics.
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spelling pubmed-65231942019-06-03 Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants Lucafò, Marianna Stocco, Gabriele Martelossi, Stefano Favretto, Diego Franca, Raffaella Malusà, Noelia Lora, Angela Bramuzzo, Matteo Naviglio, Samuele Cecchin, Erika Toffoli, Giuseppe Ventura, Alessandro Decorti, Giuliana Genes (Basel) Article The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn’s disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio (LME p = 0.041) and 30% decrease in clinical efficacy (LME p = 0.0031). GSTA1 variant (12.8% of patients) showed a trend (p = 0.046, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics. MDPI 2019-04-04 /pmc/articles/PMC6523194/ /pubmed/30987408 http://dx.doi.org/10.3390/genes10040277 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lucafò, Marianna
Stocco, Gabriele
Martelossi, Stefano
Favretto, Diego
Franca, Raffaella
Malusà, Noelia
Lora, Angela
Bramuzzo, Matteo
Naviglio, Samuele
Cecchin, Erika
Toffoli, Giuseppe
Ventura, Alessandro
Decorti, Giuliana
Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
title Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
title_full Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
title_fullStr Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
title_full_unstemmed Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
title_short Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants
title_sort azathioprine biotransformation in young patients with inflammatory bowel disease: contribution of glutathione-s transferase m1 and a1 variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523194/
https://www.ncbi.nlm.nih.gov/pubmed/30987408
http://dx.doi.org/10.3390/genes10040277
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