The pharmacogenetic basis of individual variation in thiopurine metabolism

Thiopurines are an important class of immunosuppressive therapy, which have been used in clinical practice for over 50 years. Despite this extensive experience many of the pharmacodynamic and pharmacokinetic properties of these drugs remain unknown. As a consequence there is often no clear explanation for the individual variation in response to treatment, both in terms of efficacy or adverse drug reactions. This review, which emphasizes practice in gastroenterology, summarizes the current understanding of thiopurine drug metabolism and highlights the role of nongenetic and genetic factors other than TPMT, which should be a focus for future research. Correlation of polymorphic variations in these genes with clinical outcomes is expected to clarify the basis for interindividual differences in thiopurine metabolism and enable a more personalized approach to therapy.