Pharmacogenomic And Metabolite Markers For Patients Treated With Thiopurines

The thiopurine class of drugs, which include azathioprine (a pro-drug for mercaptopurine), mercaptopurine, and thioguanine, are used to treat a variety of diseases; however, it is recommended the use of thiopurines be limited due to a high rate of drug toxicity. The TPMT and NUDT15 genes encode for the enzymes thiopurine S-methyltransferase (TPMT) and Nudix Hydrolase (NUDT15), respectively. These enzymes are involved in the metabolism of thiopurines. Genetic variants in TPMT and NUDT15 genes affect drug hydrolysis and hence, increase susceptibility to drug-induced toxicity. Mercaptopurine and thioguanine are directly metabolized by the TPMT enzyme. Susceptibility to drug toxicity is linked to the level of TPMT activity. The variation in TPMT activity has been related to 3 distinct TPMT variants. TPMT can be assessed through genetic analysis for polymorphisms in leukocyte DNA (genotype) or by measurement of the enzyme activity in circulating red blood cells (RBCs; phenotype). NUDT15 is measured by genetic analysis only (genotype). Pharmacogenomic analysis of TPMT/NUDT15 status is proposed to identify patients at risk of thiopurine drug toxicity and adjustment of medication doses accordingly. Measurement of metabolite markers has also been proposed.