TIMP can alternatively be methylated by TPMT, yielding 6‐methylthioinosine monophosphate (6‐MTIMP), 6‐methylthioinosine diphosphate (6‐MTIDP) and 6‐methylthioinosine triphosphate (6‐MTITP), forming together the methylmercaptopurine ribonucleotides (6‐MMPR). 6-MP is metabolized via a series of enzymatic steps to 6-thioguanine nucleotides (6-TGNs), to 6-methyl-mercaptopurine (6-MMPNs) by the enzyme thiopurine methyltransferase (TPMT), and to 6-thiouric acid by the enzyme xanthine oxidase (XO). 2017 Nov 27;20(1):4. doi: 10.1208/s12248-017-0161-x. ... Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving Azathioprine. In patient 8, 1 week after initiation of azathioprine, total methylated metabolite and 6‐TGN levels were also within the normal range, with 8000 and 260 pmol/8 × 108 RBC respectively (Figure 3). Lauschke VM, Milani L, Ingelman-Sundberg M. AAPS J. Steroids had been stopped 15 days before. The recent work of Mircheva et al. NUDT15 indeterminate: If thiopurines are required and NUDT15 status is unknown, monitor closely for toxicity. The American Gastroenterological Association recommends that TPMT activity should be tested prior to the start of thiopurines and the dose adjusted according to TPMT status (Feuerstein et al., 2017). In recent years, we have observed eight cases of severe pancytopenia in patients concomitantly receiving azathioprine for inflammatory bowel disease and ribavirin plus peginterferon‐alpha for chronic hepatitis C. Their TPMT genotype was normal and their myelotoxicity remained unexplained. Thiopurine methyltransferase (TPMT) is a genetically moderated key enzyme involved in the metabolism of AZA that can be used to stratify individuals into different levels of risk of developing neutropaenia. Patients with leukopenia due to azathioprine were no more likely to have abnormal TPMT enzyme levels than those without leukopenia (P=1.0). The thiopurine drugs azathioprine and mercaptopurine are well established in the treatment of Crohn's disease. AZA is a pro‐drug that is rapidly converted to mercaptopurine (MP) by a non‐enzymatic reaction in the liver. provides further evidence that azathioprine metabolism is an important factor in the therapeutic use of this active immunosuppressive agent. Overall, combination therapy with interferon plus ribavirin is poorly tolerated, with a frequent need for dose reduction, especially because of cytopenias.27 We hypothesize that the occurrence of cytopenias in this population may be favoured by the concomitant use of azathioprine and ribavirin. Adapted from Derijks et al.2 Ribavirin may increase methylated derivatives and decrease 6‐TGN levels through complete blockade of IMPDH activity (b). The eight patients did not carry any of the three common variant TPMT alleles and were considered to be wild type (TPMT*1/*1). Azathioprine is cleaved to 6-MP. Details of clinical course and evolution of azathioprine metabolites (6‐TGN and total methylated metabolites) for patients 1 and 8 are given below. As myelosuppression occurs in 1.4–7% of patients treated with azathioprine,1, 2 full blood counts should be performed weekly up to 8 weeks after initiating therapy, followed by blood tests at least every 3 months.2 Azathioprine is the prodrug of mercaptopurine, which is converted into 6‐thioinosine monophosphate (6‐TIMP). Full blood count was normal in all cases (except mild thrombopenia in patients 2, 3 and 7 related to portal hypertension) before the concomitant use of azathioprine and HCV therapy. 2018 Mar;11(2):175-181. doi: 10.1111/cts.12533. One unit of TPMT activity was equivalent to 1 nmol of 6‐methylmercaptopurine formed per hour. In two patients, a prospective monitoring of azathioprine metabolites was available. Usual doses produce blood levels of Azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). * denotes last value of azathioprine metabolites before initiation of HCV therapy. Approximately 0.3% of the population lack thiopurine s-methyltransferase (TPMT), an enzyme which helps remove thiopurine drugs such as azathioprine from the body. None of the seven patients in whom azathioprine was initiated before HCV therapy experienced haematological toxicity during azathioprine therapy (mean drug exposure duration: 3.5 ± 2.4 years, excluding patient 8). These drugs, which include 6-thioguanine, 6-mercaptopurine, and azathioprine, inhibit (suppress) the body's immune system. The enzyme thiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action. Azathioprine (2 mg/kg/day) had been introduced on 20 August 2004 for steroid‐resistant ulcerative colitis. Routine blood tests during HCV therapy revealed an abrupt decrease in platelet count (37 × 10−3/mm3), with anaemia (10.6 g/dL) and neutrophil count 1.7 × 10−3/mm3 occurring 3 weeks after the start of treatment. Hepatitis C virus infection is the most common indication for liver transplantation in the US and Europe and HCV reinfection is commonplace among transplant recipients. Genotype-Guided Thiopurine Dosing Does not Lead to Additional Costs in Patients With Inflammatory Bowel Disease. Dosage TPMT pour déterminer le risque d'accident hépatique; La vaccination contre la grippe et l'Hépatite B est très conseillée par rapport à l'accroissement du risque d'infection virale. The initial step in mercaptopurine (6MP) nucleotide metabolite formation is catalysed by hypoxanthine phosphoribosyltransferase (HPRT). Owing to its role in methylating and inactivating thiopurines (Figure 1), TPMT influences the risk of severe and potentially fatal myelosuppression among patients receiving standard doses of azathioprine or 6-mercaptopurine. High uptake of TPMT enzyme-level testing by dermatologists, compared with gastroenterologists and rheumatologists, may reflect national guidelines advocating its use prior to AZA. Myelotoxicity was accompanied by elevated total methylated metabolite levels (16 500 and 15 000 pmol/8 × 108 erythrocytes) with a concomitant decrease in 6‐tioguanine nucleotide levels; 1 month after azathioprine, pegylated interferon alfa and ribavirin were discontinued and full blood count returned to normal in both patients. 2003 Nov;15(11):1245-7. doi: 10.1097/01.meg.0000085479.12407.b8. A 53‐year‐old woman was admitted for pancytopenia on 10 September 2004. Individuals with TPMT deficiency should avoid thiopurine treatment or, if deemed nece… Azathioprine is one of the most widely used immunosuppressive agents. The thiopurines (ie, azathioprine [AZA] and mercaptopurine, also known as 6-mercaptopurine [6-MP]) exert a glucocorticoid-sparing effect for patients with inflammatory bowel disease (IBD) who cannot maintain remission when glucocorticoids are tapered or withdrawn. The full text of this article hosted at iucr.org is unavailable due to technical difficulties. Finally, all patients received azathioprine at a normal dose (2 mg/kg/day). Posologies habituelles : o AZA : 2 à 2,5 mg/kg/j o 6-MP : 1 à 1,5 mg/kg/j ! Toxicity is, in part, related to activity of the enzyme thiopurine methyltransferase (TPMT), which plays an important role in azathioprine metabolism. Some people have deficiency of TPMT because of genetic mutations. 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