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Figure 1. Thiopurine metabolism. AO: Aldehyde oxidase; AZA: Azathioprine; GDA: Guanine deaminase; GMPS: Guanosine monophosphate synthetase; GST: Glutathione-S-transferase; HPRT: Hypoxanthine guanine phosphoribosyltransferase; IMPDH: Inosine monophosphate dehydrogenase; MP: Mercaptopurine; TG: Thioguanine; TGDP: Thioguanine diphosphate; TGMP: Thioguanine monophosphate; TGN: Thioguanine nucleotide; TGTP: Thioguanine triphosphate; TIMP: Thioinosine monophosphate; TITP: Thioinosine triphosphate; TPMT: Thiopurine
S -methyltransferase; TUA: Thiouric acid; TX: Thioxanthine; TXMP: Thioxanthosine monophosphate; XO: Xanthine oxidase.
(Figure omitted. See article PDF.)
There is no better example than in thiopurine therapy to illustrate the challenges created by a narrow therapeutic index and the manifold interindividual variation in drug metabolism. Polymorphic variation in the activity of the enzyme thiopurine S -methyltransferase (TPMT) is a well-validated example of a biomarker that identifies patients at high risk of life-threatening toxicity to thiopurine drug therapy. Over the past decade, our growing understanding of the pharmacogenetics behind thiopurine drug metabolism has enabled us to become more adept with interpreting its clinical significance and influence on safer therapeutic decision making.
However, TPMT activity alone explains less than a third of thiopurine toxicity [1], while other genetic and epigenetic factors play a role in determining response to therapy. Thiopurine drug metabolite monitoring summarizes both these influences on drug metabolism.
In an era in which personalized medicine is coming to the fore, new strategies for thiopurine therapy, directed by pharmacogenetics and drug metabolite profiling, are now being used to improve clinical outcomes.
In the first part of this review, thiopurine metabolism and mechanisms of action are presented. Then, the role of TPMT in treatment, with supporting pharmacogenetic evidence, is described. Next, we discuss the influence of metabolite monitoring in thiopurine treatment decision making and highlight potential biomarkers for the future. Finally, we provide recommendations on how to apply TPMT and metabolite monitoring in clinical practice to optimize treatment.
Thiopurine metabolism & intracellular mechanisms of action
It has been over 60 years since the thiopurines were first synthesized by Nobel laureates Gertrude Elion and George Hitchings. These purine analogs, comprise mercaptopurine (MP), its pro-drug azathioprine (AZA) and 6-thioguanine (TG). They are a unique class of immunosuppressive and cytotoxic drugs, whose first application was in the treatment of acute leukemia in children in the 1950s [2]. Since then, their use has expanded across a multitude of medical conditions...