Non‐detectable levels of 6‐thioguanine nucleotides and 6‐methylmercaptopurine in a patient treated with azathioprine: a case report

Abstract

Introduction: Azathioprine (AZA) is a thiopurine prodrug clinically used for immunosuppression in the treatment of auto‐immune inflammatory diseases and in regimens of organ transplantations. The pharmacological action of AZA is based on the formation of 6‐mercaptopurine (6‐MP), which is metabolised into a variety of active thiopurine‐nucleotide metabolites. We report the case of a 55 year old woman (bodyweight 30 kg) with chronic pancreatitis, weight loss, and progressive elevation of liver transaminases and serum amylase.Case description: The woman was treated with prednisolone (30 mg 1 dd; tapered 5 mg each week) and AZA (75 mg 1 dd; 5 weeks later 150 mg 1 dd). Despite good patient‐compliance verified during hospital‐stay, none of the active metabolites of AZA, 6‐thioguanine‐nucleotides (6TGN) and 6‐methylmercaptopurine ribonucleotides (6MMPR), were detected in erythrocytes. After two months of treatment clinical improvement was achieved, but no normalisation of laboratory parameters. Subsequently, AZA was switched to 6‐MP 75 mg 1 dd, and allopurinol 100 mg 1 dd was added. After one week the 6TGN level was 616 pmol/ 8 × 108 red blood cells (RBC), the 6MMPR level was 1319 pmol/ 8 × 108 RBC.Two weeks later the 6TGN level was 1163 pmol/ 8 × 108 RBC and the 6MMPR level 10015 pmol/ 8 × 108 RBC.These 6TGN and 6MMPR levels were higher than the upper limits of the therapeutic ranges (500 pmol/ 8 × 108 RBC and 5700 pmol/ 8 × 108 RBC, respectively). Therefore, treatment with 6‐MP was discontinued. A week later the 6TGN and 6MMPR levels decreased to 686 pmol/ 8 × 108 RBC and 4027 pmol/ 8 × 108 RBC, respectively.Genotyping of the enzym thiopurine S‐methyl transferase (TPMT) revealed a wild‐type TPMT (*1/*1) genotype.Discussion: To our knowledge this is the first report of a patient who was not able to form detectable active thiopurine metabolites on the treatment with AZA.AZA is normally rapidly and almost completely converted to 6‐MP and methylnitroimidazole in the liver. 6‐MP is then further catabolised by xanthine‐oxidase (XO) and TPMT or anabolised by hypoxanthine phosphoribosyl transferase (HPRT). Remarkably, treatment with 6‐MP in combination with the XO‐inhibitor allopurinol resulted in a myelotoxic 6TGN level in the first week after start of treatment.There are two hypotheses on the mechanism by which this finding could be explained. First, an ‘ultra‐high’ XO activity results in a direct and complete conversion of 6‐MP into 6‐thiouric acid. Secondly, AZA is not converted into 6‐MP. Consequently, there is no formation of active thiopurine nucleotides out of 6‐MP.Also, a combination of these two mechanisms could lead to a decreased formation of active thiopurine metabolites.Conclusion: Our finding indicates non‐conventional insights in the biotransformation of AZA contributing to an interindividual variation in thiopurine metabolism.