Interactions between principal cytotoxic thiopurine metabolites, that is 6-thioguanine nucleotides [6-TGN], and infliximab [IFX] and anti-IFX antibodies [Abs] may contribute to higher effectiveness of IFX-thiopurine combination therapy than monotherapies in inflammatory bowel disease.
Finally, we found that the range of 6-TGN concentrations in autoimmune diseases was much lower than the established 6-TGN monitoring range for inflammatory bowel diseases.
TPMT genotype and thiopurine metabolite monitoring could be helpful to examine TPMT genotypes before administering AZA and to measure 6-TGN concentrations during prescribing AZA in IBD patients.
Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0-14.0 and ≤4, respectively, were assessed by hybridization to microarrays.
Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04).
IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤ 20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity.
In inflammatory bowel disease (IBD), 6-TGN levels in the target range of 235-400 pmol/8x10(8) red blood cells (RBC) are associated with a high likelihood of response.
Initial target doses to attain therapeutic 6-TGN concentrations (>235 pmol/8 x 10(8) RBCs) in patients with IBD might be 1 and 3 mg/kg/d in intermediate and normal metabolizers, respectively.
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.