Medicine of the Future in America

Category Archives: Thiopurine methyltransferase enzyme

Thiopurine methyltransferase enzyme activity determination: Discussion (Part 3)

One could hypothesize that knowing a normal TPMT activity would eliminate the need for routine testing and, thereby, significantly reduce costs. Unfortunately, this is unlikely to be the case, because this and other studies have demonstrated myelotoxicity and hepatotoxicity in the presence of normal TPMT activity. Physicians are thus likely to continue to perform hematological and biochemical testing on a regular basis .

None of the patients in the present study were homozygous for TPMT deficiency. It has recently been suggested that TPMT genotyping would be cost-effective in identifying the one in 300 individuals homogenous for TPMT deficiency. Indeed, it is this group in whom acute and severe myelosuppression is most frequent and has led to the current clinical practice of subtherapeutic dosing and frequent biochemical monitoring. Continue reading

Thiopurine methyltransferase enzyme activity determination: Discussion (Part 2)

TPMT genotypeTPMT activity can be influenced not only by TPMT genotype but by concomitant medications. TPMT activity can be inhibited by sulfasalazine, olsalazine, balsalazide, mesalamine and, to a lesser extent, by furosemide, thiazide diuretics and nonsteroidal anti-inflammatory drugs. Thus, the concomitant use of mesalamine could lead to increased toxicity. Seven patients in the present study were using mesalamine concomitantly with AZA. None of the patients on mesalamine developed AZA-related adverse events.

In the present study, the prospective assessment of TPMT enzyme activity before the initiation of AZA therapy for patients with IBD in group 2 was associated with increased direct cost ($348.87 per patient) compared with group 1 ($300.11 per patient), in which the TPMT assay was not performed. Continue reading

Thiopurine methyltransferase enzyme activity determination: Discussion (Part 1)

Knowing TPMT activity and starting AZA in either a ‘step-in’ or ‘step-up’ approach did not alter the number of adverse events related to AZA nor the number of withdrawals from the study. This is likely because most of the adverse events necessitating withdrawal were those that are generally thought to be independent of AZA metabolite levels . One patient developed leukopenia and two patients developed elevated liver enzymes in the group in which TPMT activity was not initially known (group 1; ‘step-up’ AZA dosing); however, retrospective testing confirmed normal TPMT activity in these patients. Continue reading

Thiopurine methyltransferase enzyme activity determination: Results (Part 3)

steroid-refractory IBDPatients in group 1 initiated a total of nine phone calls to their physicians or nurses to discuss the AZA therapy, while patients in group 2 initiated 11 such calls. Only one additional unscheduled doctor visit occurred in group 1, in a patient presenting with jaundice and hepatitis.

It is well established that 6-MP, and its prodrug AZA, are effective in the treatment of steroid-refractory IBD and in the maintenance of steroid-induced remission. What is less clear, however, is the role of TPMT activity, the key enzyme responsible for the metabolism of AZA into toxic and therapeutic metabolites, in the management of IBD. Continue reading

Thiopurine methyltransferase enzyme activity determination: Results (Part 2)

One patient in group 2 developed clinical pancreatitis (lipase 2912 U/L) two weeks after starting the drug and was withdrawn. Two patients in group 2 withdrew from the study at 1 and 3.6 months because the AZA provided no therapeutic effects. Patients in group 1 withdrew at a mean of 2.7±2.8 months (range 0.4 to 8.0 months) after initiation of the drug therapy, while patients in group 2 withdrew at a mean of 1.6± 1.4 months (range 0.2 to 4.0 months). For the 13 patients still in the study at its termination, mean follow-up was 8.0±2.3 months (range 3.5 to 10.7 months). Continue reading

Thiopurine methyltransferase enzyme activity determination: Results (Part 1)

packed erythrocytesResults are expressed as nmol of 6-MMP produced per mL of packed erythrocytes per hour of incubation at 37°C. If the samples were not assayed immediately, they were stored at -70°C. However, all samples were assayed within four days of collection. Repeat analysis of one sample showed an interassay precision of 100% over the course of the study.

Of the 29 patients enrolled in the study, 15 were randomized to group 1 and, thus, did not have their TPMT activity determined. The remaining 14 were randomized to group 2, and their TPMT activity tested as normal. The demographics of the groups were similar except for the difference in sex between the two groups. Continue reading

Thiopurine methyltransferase enzyme activity determination: Measurement of TPMT activity

Direct health care costs, including the cost of the TPMT assay, scheduled laboratory investigations and nonscheduled diagnostic investigations were recorded. The TPMT assay was valued at $50.00, and the local regional laboratory and provincial billing guidelines were used to determine the value of laboratory and diagnostic investigations (Table 2). Telephone calls to nurses and visits to a physician because of side effects or consequences of AZA treatment were also recorded and valued according to local provincial billing guidelines (Table 2). Continue reading

Thiopurine methyltransferase enzyme activity determination: Patient population

complete blood countBefore starting AZA, the 29 patients were prospectively randomized to one of two groups. Group 1 (n=15) did not have the TPMT assay performed; they were started on AZA at 1 mg/kg/day, and the dose was titrated upwards by 50 mg every two weeks to a target dose of 2.5 mg/kg/day. Group 2 (n=14) had the TPMT assay performed before starting AZA. All 14 patients in group 2 had normal TPMT levels (greater than 9 nmol/mL red blood cells) and started AZA at the target dose of 2.5 mg/kg/day. Continue reading

Thiopurine methyltransferase enzyme activity determination (Part 4)

We therefore sought to determine whether the assessment of TPMT activity before administration of AZA would predict toxicity and could therefore be used to reduce the costs related to the standard biochemical screening for, and management of, AZA-induced adverse events. The present study was performed between September 2002 and August 2003, and was approved by the Health Research Ethics Board at the University of Alberta, Edmonton, Alberta. Twenty-nine patients aged 12 years and older with either CD (23 patients) or ulcerative colitis (six patients) who were starting AZA treatment were recruited for this randomized prospective study. Continue reading

Thiopurine methyltransferase enzyme activity determination (Part 3)

TPMT activityThe lower the inherited TPMT activity, the more 6-MP is available for conversion to toxic thiopurine nucleotide metabolites and the higher the myelotoxicity. In TPMT-deficient patients, high concentrations of 6-TG nucleotides accumulate in hematopoietic tissue, thereby contributing to toxicity. In the case of IBD, increased 6-TG levels may correlate positively with increased clinical responses and leukopenia . The accumulation of the end products of TPMT activity, including 6-MMP nucleotide metabolites, has been implicated as a cause of hepatotoxicity. Clinically, TPMT activity can be measured using the red blood cell TPMT assay, which reveals TPMT activity in leukocytes, and in liver and kidney cells. Continue reading

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