Monitoring of Thiopurine Methyltransferase Activity in Postsurgical Patients With Crohn's Disease During 1 Year of Treatment With Azathioprine or Mesalazine

Abstract

Thiopurine methyltransferase (TPMT) activity determines biotransformation of azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine or azathioprine on TPMT activity is of particular clinical importance because both drugs can to be given for several years in inflammatory bowel disease. Monitoring of TPMT activity and three thiopurine metabolites was performed prospectively during a 1 year postoperative period in 21 patients with Crohn's disease randomly assigned to azathioprine (2.0-2.5 mg/kg per day) or mesalazine (4 g/day). TPMT activity did not change significantly within each treatment group during 52 weeks. At any study visit, TPMT activity was not different between 13 patients on azathioprine and eight patients on mesalazine. Concentrations of 6-thioguanine nucleotides (6-TGN, active moiety of azathioprine) and 6-methyl-mercaptopurine ribonucleotides (6-MMPR) did not alter significantly during the observation period, except for a slight decrease in 6-TGN levels when comparing the first with the last visit. In this first report of serial monitoring of 6-methyl-thioguanine nucleotides (6-MTGN) in patients with inflammatory bowel disease taking azathioprine, high levels of 6-TGN were correlated with high levels of 6-MTGN, with the mean 6-TGN:6-MTGN ratio being 2.4. In a well-standardized clinical setting of inflammatory bowel disease, neither mesalazine nor azathioprine significantly affected TPMT activity during a whole year of treatment.

The development of an objective methodology to measure medication adherence to oral thiopurines in paediatric patients with acute lymphoblastic leukaemia—an exploratory study

“…This may indicate that patients need some time to report non-adherence, reflecting the importance of confidence and assurance that the patients should receive from the person who is administering the questionnaire. It is also possible that patients are more likely to adhere to their medication at the start of the study but lose their adherence toward the end, as reflected by a decline in 6-TGNs and 6-mMPNs in a recent study by Dilger et al [25].…”

“…Hierarchical cluster analysis was used to identify cut-off points of 6-TGNs and 6-mMPNs that may indicate non-adherence to therapy [<14 and <104 pmol/(8×10 8 RBCs) mg −1 m 2 for 6-TGNs and 6-mMPNs respectively]. The idea of cluster analysis in relation to 6-MP active metabolites has been applied in only one study before [25], but it was used to identify patients at risk of suboptimal drug therapy rather than non-adherence. In addition, it was limited to adolescent subjects with ALL and, unfortunately, did not provide information on patient's genotypes or whether patients belonged consistently to one cluster or another over serial samples.…”

Interruption of Mesalamine and Reduction of the Blood Concentration of the Active Metabolites of Azathioprine: Possible Causes of Ulcerative Colitis Relapse

“…One possible explanation for the continued low ratio is that the ratio of MMPN to TGN is affected by the genotypes of the enzymes involved in azathioprine or mesalamine metabolism. Future studies should focus on the factors affecting this ratio [10,18].…”

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

“…This synergism between the two drugs has been shown to mainly increase the concentrations of 6-TGDP and 6-TGTP [125]. Moreover, it has been reported in vitro that co-prescription of 5-ASA inhibits the enzyme activity of TPMT and decreases the 6-MeMP level [85,126], although these findings are controversial in vivo [123,125,127].…”