Prospective Study of the Effects of Concomitant Medications on Thiopurine Metabolism in Inflammatory Bowel Disease

M. Daperno; R. Sostegni; R. Canaparo; L. Serpe; A. Lavagna; L. Crocellá; F. Castagno; A. Vernetto; C. Rigazio; E. Ercole; S. D'Antico; A. Pera; G. Zara; R. Rocca

Disclosures

Aliment Pharmacol Ther. 2009;30(8):843-853. 

In This Article

Abstract and Introduction

Abstract

Background Thiopurines are increasingly used in the treatment of inflammatory bowel disease (IBD), being the most common immunosuppressive therapy; however, potentially harmful interactions between thiopurines and other drugs (especially 5-aminosalicylic acid, 5-ASA) were described.
Aim To explore potential interactions between thiopurines and concomitant medications.
Methods A total of 183 consecutive IBD patients were enrolled. Clinical characteristics and concomitant medications were recorded. Thiopurine metabolism was analysed with thiopurine S-methyl transferase (TPMT) genetic variants and enzyme activity assays. Comparisons were carried out with stratification of patients according to clinical characteristics and active treatments.
Results Based on TPMT genetics, 95% IBD patients were wild-type homozygous, the remaining being heterozygous. Median TPMT activity was 24.9 U/Hgb g (IQR 20.7–29.5). No difference in TPMT activity was noted according to 5-ASA exposure. IBD patients on thiopurines had higher TPMT activity levels, but no dose-effect was evident. No difference in TPMT activity was observed in 41 (63%) patients co-treated with 5-ASA. In patients on active thiopurines also, 6-TGN and 6-MMP levels were evaluated and no significant difference was observed based on co-medication. TPMT activity was independently associated only with thiopurines dose (P = 0.016).
Conclusions Our data suggest the absence of significant interactions between thiopurines and 5-ASA.

Introduction

Thiopurines (azathioprine and mercaptopurine) are extensively used in clinical practice and their use in inflammatory bowel disease (IBD) has increased over the last decades.[1,2] The effect on clinical outcomes is still a matter of debate, but current guidelines and everyday routine clinical practice include azathioprine or mercaptopurine among the most commonly used drugs, especially because of their steroid-sparing effect.[3–6] Moreover, their use, together with infliximab, has been advocated and they are therefore an essential therapeutic weapon.[7]

Metabolism of azathioprine is quite well-known and it includes, after a non-enzymatic step leading to mercaptopurine formation, several enzymatic transformations leading to formation of active metabolites, of toxic intermediate molecules and finally to complete catabolism of the drug. One of the most important steps in thiopurine metabolism is under thiopurine S-methyl-transferase (TPMT, EC 2.1.1.67) control. TPMT is a cytosolic enzyme which catalyses the S-methylation of aromatic and heterocyclic sulphydril compounds.[8] This enzyme represents one of the most striking examples of the potential of pharmacogenetics to contribute to personalize drug therapy with 89–94% of individuals having high TPMT activity, 6–11% having intermediate activity and approximately 0.3% with extremely low or absent TPMT activity.[9] Family studies have shown that TPMT activity is inherited as an autosomal codominant trait, with at least 21 TPMT genetic polymorphisms identified, which may be associated with decreased levels of TPMT enzyme activity and/or thiopurine drug-induced toxicity.[10] Many population studies were carried out to identify the predominant variant alleles and, on the basis of these researches, TPMT*3A and *3C are the predominant variant alleles, with *2 contributing to a lesser extent. These three alleles account for over 95% of cases of inherited TPMT deficiency in Caucasian subjects.[11]

Five-aminosalicylic acid (5-ASA) is very commonly used in inflammatory bowel disease. Its role is essential in ulcerative colitis treatment, both in induction and in maintenance of remission;[6] moreover, despite its limited efficacy, 5-ASA is used also in Crohn's disease, especially for prevention of post-surgical relapse.[5] Finally, another therapeutic goal, which justifies a wide use of 5-ASA, is the potential chemopreventive role in IBD colitis.[12] A recent population-based study reported an overall prevalence of oral 5-ASA use in up to 75% IBD patients in Northern Italy.[13]

Some Literature data showed that 5-ASA may lower TPMT activity, thus leading to increased bioavailability of upstream metabolites, with potential toxic effects and/or potential therapeutic gain.[14–16] In vitro experiments reported substantial inhibition of TPMT activity or effects on thiopurine active metabolites by sulphasalazine or 5-ASA.[17–19] Consistent with these in vitro data, a few clinical reports suggested that there may be a significant interaction between 5-ASA and TPMT also in vivo and such an interaction may be used to maximize thiopurine therapeutic window.[20–22]

The aims of the study were to analyse in a consecutive series of IBD patients:

  1. overall TPMT activity and

  2. the effects of thiopurine, 5-ASA and other concomitant IBD medications on TPMT activity and on metabolites levels

to evaluate relevant interactions clinically.

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