Importance of 6-Thioguanine Nucleotide Metabolite Monitoring in Inflammatory Bowel Disease Patients Treated with Azathioprine

Abstract

The active metabolite of azathioprine, 6-thioguanine nucleotide (6-TGN) is the main component responsible for the immunosuppressive effect in treatment of inflammatory bowel disease (IBD). The aim of this study was to assess the correlation between the concentration of 6-thioguanine nucleotide and disease activity, azathioprine-related adverse effects and time duration of treatment in patients with inflammatory bowel disease. Thirty-four patients were included in this study. Type of disease, gender, time duration of therapy and adverse effects were recorded. Metabolite concentration was determined by high performance liquid chromatography. Twenty-one percent of patients have experienced an adverse effect, with leucocytopenia most commonly occurring (42.9%). More adverse effects were registered when patients were treated with azathioprine in a period of less than 3 months in comparison to the group of patients that have been under therapy between 3-12 months and more than 12 months (p˂0.05). Most of the patients that presented any adverse effect had high 6-TGN concentration (>450 pmol/8x108 Er). The mean value of 6-TGN metabolite concentration in IBD patients treated with azathioprine was 437.46 pmol/8x108 Er ± 198.82 pmol/8x108. The time duration of azathioprine treatment did not have any significant impact on the achieved 6-TGN concentration (p>0.05).Twenty patients (58.9%) had achieved remission after therapy initiation with azathioprine. More alertness is recommended to clinicians towards patients in the first 3 months of the therapy. Our study demonstrated that higher 6-TGN concentration is associated with azathioprine toxicity.

Usefulness of Measuring Thiopurine Metabolites in Children with Inflammatory Bowel Disease and Autoimmunological Hepatitis, Treated with Azathioprine

“…That observation was similar to that in another study [26]. On the contrary, Pavlovska et al reported a higher percentage of adverse effects [24]. The most common treatment-related complication was leucocytopaenia (42.9%), followed by elevated transaminase levels (28.6%), aphthous ulcers (14.3%), and elevated amylase in serum (14.3%).…”

“…As in some other studies, we did not find any correlation between thiopurine dose and 6-TGN levels; therefore, increasing the drug dose may not be sufficient to reach the desired 6-TGN target [ 24 , 26 ]. This may be explained by an increased methylation of intermediate 6-MP metabolites by inherited high levels of TPMT activity [ 5 ].…”

“…In a study by Lee et al [ 23 ], the occurrence of leucocytopaenia and lymphopenia was associated with high concentrations of 6-TGN. Also, Pavlovska et al showed similar results [ 24 ]. However, we did not observe this correlation in our study; the possibility of serious side effects should be considered in case of high 6-TGN levels.…”

Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis

“…It is well known that 6-TGN is the active metabolite responsible for AZA efficacy and cytotoxicity, and one of the side effects of AZA therapy is myelosuppression. Therapeutic drug monitoring (TDM) of one of the pharmacologically active metabolites of thiopurines, 6-TGN, has proven beneficial 36 . However, there is no unified conclusion about the relationship between the concentration of 6-TGN in red blood cells and adverse reactions.…”

Association of Genetic Variants in TPMT, ITPA, NUDT15 With Azathioprine-Induced Myelosuppression in Southwest China Patients With Autoimmune Hepatitis

“…Therapeutic drug monitoring (TDM) of the pharmacologically active metabolites of thiopurines, 6-TGN, has proven bene cial. 33 However, there is no uni ed conclusion about the relationship between the concentration of 6-TGN in red blood cells and adverse reactions. In the research of Asada et al 12 and Xiang Fei et al 29 , there was no statistically signi cant concentration difference observed between different NUDT15c.415C > T genotypes.…”