Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

Abstract

SUMMARY BackgroundAzathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of biomarkers to predict adverse effects and therapeutic response is paramount.

Polymorphic Variation in TPMT Is the Principal Determinant of TPMT Phenotype: A Meta‐Analysis of Three Genome‐Wide Association Studies

“…ALL in childhood, IBD, autoimmune diseases) 19,20 pretreatment determination of the TPMT phenotype and subsequent pharmacogenetically-guided dosing of thiopurines, at least in TPMT deficient individuals, is recommended in routine clinical practice before commencing therapy. 5 Very recently a landmark randomized clinical trial strongly corroborates the clinical utility of upfront genetic testing for TPMT in patients treated with thiopurines to avoid hematotoxicity.…”

Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease

“…14 Measurement of pretreatment TPMT activity and metabolites while on treatment reduces the risk of adverse events and improves efficacy by up to 7% and 30%, respectively. 15 About 1 in 300 are missing the genes to produce any TPMT, about 11% are heterozygous for the wild type, and nearly 89% are homozygous for the wild type who produce high levels of TPMT. Although there are reports of AZA treatment success in TPMT-deficient leukemic children whose serum levels were intesnsely monitored, thiopurines are best avoided in the homozygous mutant population to avoid potentially lethal myelosuppression.…”

Microbiota: relevant player in thiopurine metabolisation?

“…Furthermore, methylated metabolites generated by thiopurine S-methyltransferase (TPMT) activity have been identified as mediators of side effects in patients treated with azathioprine. Finally, systemic thiopurine administration may result in an increased susceptibility towards severe bacterial or viral infections due to general immunosuppressive effects 9. Remarkably, Oancea et al now provided data that strongly encourage the idea of topical thioguanine administration and thereby open new avenues to overcome the apparent inseparability of thiopurine efficacy and toxicity.…”

“…Indeed, the activities of all master enzymes included in thiopurine metabolism (xanthine oxidase, TPMT, hypoxanthine phosphoribosyltransferase (HPRT) and inosine monophosphate dehydrogenase) show marked variations among individuals, which relevantly impact on the efficacy of active thiopurine formation 9. So, it is well known that, for instance, low TPMT activity results in an overwhelming generation of active TGN metabolites and is therefore associated with an increased risk for myelosuppressive side effects, while, vice versa, high TPMT activity favours the formation of inactive methylated metabolites and potentially goes along with non-responsiveness9 (figure 1). In a similar way, increased activity of the activating enzyme HPRT turned out to be associated with marked effects on leucocytes in thiopurine-treated patients with IBD 9.…”

“…So, it is well known that, for instance, low TPMT activity results in an overwhelming generation of active TGN metabolites and is therefore associated with an increased risk for myelosuppressive side effects, while, vice versa, high TPMT activity favours the formation of inactive methylated metabolites and potentially goes along with non-responsiveness9 (figure 1). In a similar way, increased activity of the activating enzyme HPRT turned out to be associated with marked effects on leucocytes in thiopurine-treated patients with IBD 9. The main advantage of the now-described capacity of intestinal microbial or mucosal enzymes to catalyse a host-independent thioguanine metabolisation is again related to the resulting applicability of topical administration strategies and the subsequent prevention of systemic metabolite accumulation.…”