Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease

Lowry, Philip W.

doi:10.1136/gut.49.5.665

Cited by 217 publications

(149 citation statements)

References 20 publications

(29 reference statements)

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…These results are similar to those found by Ref. [8,28]. However, it is interesting to find that by Cont W1 phase, a negative correlation was attained between TGNs and WBCs and neutrophils (r=-0.485, p=0.093 and r=-0.455, p=0.118 respectively), in a similar finding to Lennard et al [10] (Figure 6A).…”

Section: Tgn and Hematological Toxicitysupporting

confidence: 91%

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

Abdelsayed¹,

A²,

Sidhom³

et al. 2017

J Anal Bioanal Tech

View full text Add to dashboard Cite

The need of a robust, sensitive HPLC method for the quantitation of 6-thioguaninenucleotides (6-TG) and 6-methylmercaptopurine (6-MMP) is indispensable to relate levels of these metabolites with emergence of signs of toxicity in patients undergoing treatment with 6-mercaptopurine (6-MP), paving the road to accurate dose calculations and thus providing a cost-effective treatment approach. Previously reported methods were either laborious, required special types of C18 columns, or had long run times. A Design of Experiments (DoE) approach targeting the shortest run time with greatest selectivity was adopted using a user friendly HPLC method development simulation software (DryLab®). Analytes eluted within 10 min, at 3.8, 4.2, 5.6 and 7.5 min for 6-TG, 6-MP, 6-MMP and Dithiothreitol (DTT) respectively. Excellent recovery percentages of 90.9 ± 14.4, 87.8 ± 6.7 and 92.1 ± 9.08, respectively were obtained. The method proved its validity and robustness according to the International Conference on Harmonization (ICH) guidelines. The LOD of 6-MP, 6-TG and 6-MMP were 6, 9 and 24 pmol/8 × 108 RBCs, respectively. Twenty-Two Acute Lymphocytic Leukemia (ALL) children recruited from 57357 Cancer Hospital (Cairo, Egypt) had their 6-MP metabolites measured using the developed method. A strong negative correlation was manifested between TG and RBCs count and hemoglobin (p=0.009 and 0.002 respectively). WBC and neutrophils showed a negative correlation to TG at Continuation 1 phase of treatment, confirming the association of TG with myelotoxicity. The significant correlation between MMP and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (p=0.030, 0.004) explained its potential hepatotoxicity.

show abstract

Section: Tgn and Hematological Toxicitysupporting

confidence: 91%

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

Abdelsayed¹,

A²,

Sidhom³

et al. 2017

J Anal Bioanal Tech

View full text Add to dashboard Cite

show abstract

“…Unfortunately, published studies are con£icting as to the role of TGN measurements. 20,71,73^76 From the IBD literature, the suggestion is that levels greater than 235 or 250 pmol/mL RBC are associated with good response 20,74 but other studies have not found this 73,76 Heterogeneity amongst groups of patients and de¢ni-tions of clinical response make the interpretation of TGN data very di⁄cult. Perhaps more importantly, the methodology for measurement of TGNs and whether total or individual TGNs are the best marker needs further evaluation before measurement can be recommended for routine clinical practice.…”

Section: Measurement Of Tgns On Thiopurine Therapymentioning

confidence: 99%

Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy?

et al. 2004

View full text Add to dashboard Cite

Thiopurines [azathioprine (AZA), 6-mercaptopurine (6-MP) and thioguanine (6-TG)] have a well-established role as immunosuppressive agents in a variety of chronic inflammatory conditions, haematological neoplasia and in transplant rejection. Despite good overall clinical response rates, particularly when used as steroid sparing agents, adverse effects are a limiting problem leading to withdrawal in up to a quarter of patients. Severe myelosuppression is the most serious toxicity occurring early or occasionally later during treatment.An understanding of the competing pathways involved in the metabolism of thiopurines has important implications for predicting some of the more severe toxicity seen with these drugs. Thiopurine methyl transferase (TPMT) is an enzyme catalysing the methylation of 6-MP, competing with xanthine oxidase (XO) and hypoxanthine guanine phosphoribosyl transferase (HGPRT) to determine the amount of 6-MP metabolised to cytotoxic thioguanine nucleotides. Allelic polymorphisms in the TPMT gene predict the activity of the enzyme such that 1 in 10 of the population are heterozygous and have approximately 50% of normal activity, whilst 1 in 300 are completely deficient. As a result, these individuals are at high risk of severe myelosuppression. Conversely, individuals with very high levels of TPMT activity are hyper-methylators in whom clinical response is less likely.Prior knowledge of TPMT status avoids exposure of individuals with zero TPMT to potentially fatal treatment with AZA or 6-MP and provides one of the best examples of predictive pharmacogenetics in therapeutics. This article reviews literature on the role of TPMT measurement prior to treatment with thiopurines and provides some guidance to the use of TPMT as a guide to tailoring thiopurine therapy.

show abstract

“…These individuals were not treated with thiopurines; one, however, was treated with an aminosalicylate. There have been studies that indicate a modest reduction in TPMT activity in some patients during treatment with aminosalicylates compared with TPMT activity at baseline (35)(36)(37)(38)(39). For an individual with a heterozygous genotype to present a low-activity phenotype, the aminosalicylate treatment would have to cause a reduction in TPMT activity up to 15-fold.…”

Section: Clinical Materialsmentioning

confidence: 99%

Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease

Haglund

Lindqvist²,

Almér

et al. 2004

Clinical Chemistry

View full text Add to dashboard Cite

Background: Interindividual differences in therapeutic efficacy in patients treated with thiopurines might be explained by the presence of thiopurine S-methyltransferase (TPMT) alleles that encode for reduced TPMT enzymatic activity. It is therefore of value to know an individual's inherent capacity to express TPMT. Method: We developed a pyrosequencing method to detect 10 single-nucleotide polymorphisms (SNPs) in TPMT. A Swedish population (n ‫؍‬ 800) was examined for TPMT*3A, TPMT*3B, TPMT*3C, and TPMT*2. Patients with inflammatory bowel disease (n ‫؍‬ 24) and healthy volunteers (n ‫؍‬ 6), selected on the basis of TPMT enzymatic activity, were investigated for all 10 SNPs to determine the relationship between TPMT genotype and phenotype. Results: In the general population we identified the following genotypes with nonfunctional alleles:

show abstract

Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease

Cited by 217 publications

References 20 publications

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy?

Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease

Contact Info

Product

Resources

About