Azathioprine and 6‐mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease

Abstract

The thiopurine drugs azathioprine and 6-mercaptopurine (6-MP) are well-established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter- and intra-patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9-25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life-threatening myelotoxicity in the one in 300 patients who are TPMT-deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6-Thioguanine nucleotides (6-TGN) are thought to be the predominant active metabolites of the thiopurines. 6-thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6-TGN and 6-methylmercaptopurine (6-MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non-compliance, under-dosing, thiopurine-resistant and thiopurine-refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD.

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

“…[12][13][14] It has an anti-proliferative effect on T cells. One of the hypotheses explaining its antiinflammatory effect is that a metabolite of AZA, 6-thioguanine (6TG) accumulates in lymphocytes and blocks expression of cytokines which mediate inflammation.…”

“…One of the hypotheses explaining its antiinflammatory effect is that a metabolite of AZA, 6-thioguanine (6TG) accumulates in lymphocytes and blocks expression of cytokines which mediate inflammation. 12,15 The metabolism of AZA is complex and involves many enzymatic pathways 14 (Figure 1a). After getting absorbed from the gastrointestinal tract, $85-90% of AZA is nonenzymatically converted to 6MP.…”

“…After getting absorbed from the gastrointestinal tract, $85-90% of AZA is nonenzymatically converted to 6MP. 14,15 Thereafter, 6MP is either converted to 6-thiouric acid by xanthine oxidase (XO) or to 6-methyl mercaptopurine (6MMP) after methylation by thiopurine methyltransferase (TPMT) or into thioinosine monophosphate (TIMP) by hypoxanthine guanine phosphoribosyl transferase (HGPRT). TIMP is then converted to 6TG.…”

Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

“…RBC 6-TGN concentrations are inversely related to levels of TPMT enzyme activity and are directly related to drug-induced toxicity (Lennard et al, 1987(Lennard et al, , 1989. Therefore, serial RBC 6-TGN assays have also been used to monitor thiopurine efficacy and/or toxicity (Gearry and Barclay, 2005). As a result, debate continues with regard to whether or when to assay RBC TPMT enzyme activity, RBC 6-TGN concentrations, TPMT genotype -or some combination of all three -in the clinic.…”

“…As a result, debate continues with regard to whether or when to assay RBC TPMT enzyme activity, RBC 6-TGN concentrations, TPMT genotype -or some combination of all three -in the clinic. That question remains to be resolved, although genotyping or phenotyping to prevent exposure of patients with very low TPMT to standard doses of thiopurine drugs is finding increasing clinical acceptance (Gearry and Barclay, 2005).…”