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Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease
BACKGROUND: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9802184/ https://www.ncbi.nlm.nih.gov/pubmed/36776499 http://dx.doi.org/10.1093/crocol/otaa058 |
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author | Jonason, David E Sievers, Tyson Trocke, Lindsay Abraham, James M Vaughn, Byron P |
author_facet | Jonason, David E Sievers, Tyson Trocke, Lindsay Abraham, James M Vaughn, Byron P |
author_sort | Jonason, David E |
collection | PubMed |
description | BACKGROUND: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population. METHODS: A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects. RESULTS: One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 10(8) red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 10(8) RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 10(8) RBCs, interquartile range: 94.3, 287.8), though not significantly (P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration. CONCLUSIONS: Variations within the normal range of TPMT activity do not affect 6-TGN concentration. |
format | Online Article Text |
id | pubmed-9802184 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-98021842023-02-10 Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease Jonason, David E Sievers, Tyson Trocke, Lindsay Abraham, James M Vaughn, Byron P Crohns Colitis 360 Observations and Research BACKGROUND: Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population. METHODS: A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects. RESULTS: One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 10(8) red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 10(8) RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 10(8) RBCs, interquartile range: 94.3, 287.8), though not significantly (P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration. CONCLUSIONS: Variations within the normal range of TPMT activity do not affect 6-TGN concentration. Oxford University Press 2020-07-11 /pmc/articles/PMC9802184/ /pubmed/36776499 http://dx.doi.org/10.1093/crocol/otaa058 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Observations and Research Jonason, David E Sievers, Tyson Trocke, Lindsay Abraham, James M Vaughn, Byron P Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease |
title | Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease |
title_full | Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease |
title_fullStr | Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease |
title_full_unstemmed | Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease |
title_short | Normal Ranges of Thiopurine Methyltransferase Activity Do Not Affect Thioguanine Nucleotide Concentrations With Azathioprine Therapy in Inflammatory Bowel Disease |
title_sort | normal ranges of thiopurine methyltransferase activity do not affect thioguanine nucleotide concentrations with azathioprine therapy in inflammatory bowel disease |
topic | Observations and Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9802184/ https://www.ncbi.nlm.nih.gov/pubmed/36776499 http://dx.doi.org/10.1093/crocol/otaa058 |
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