Improving Patient Outcomes Through Better Understanding of Thiopurine Metabolism

Abstract

The thiopurine pro-drugs, azathioprine (AZA) and 6-mercaptopurine (6MP), are employed to maintain remission in inflammatory bowel diseases (IBD) because they are effective and economical treatments in 60% of patients. However, they are frequently associated with treatment-limiting adverse drug reactions (ADR), and therefore 6-thioguanine (6TG) has been proposed as an alternative thiopurine therapy in the treatment of IBD. 6TG has a faster onset of action, less dose-independent ADR and it exerts a good clinical response, but it has been frequently implicated with the serious ADR of hepatic nodular regenerative hyperplasia and/or veno-occlusive disease. The term, sinusoidal obstructive syndrome (SOS), was recently coined to describe the underlying vascular pathology. SOS is usually clinically silent until development of portal hypertension. Animal models with SOS have been previously described, in rats after monocrotaline (MC) administration and in dogs after treatment with a generation II proton pump inhibitor, but no animal model of SOS after thiopurine treatment is known. SOS has been described with AZA/6MP, and some clinicians have suggested that it is a thiopurine class effect, but mainly was associated with 6TG. There is controversy about whether thiopurine associated SOS is: i) 6TG specific or a thiopurine class effect; ii) idiosyncratic or 6TG dose-related. We report on a novel model of SOS due to 6TG. We show that the SOS pathology is dose-related, is not a thiopurine class effect, is mediated principally by thioguanosine nucleotides, and is amplified by inflammatory leukocytes entering the liver. A novel scoring system defining SOS was created based on pathology of the central vein, sinusoids and perivenular parenchyma. Wildtype, hypoxanthine-guanine phosphoribosyltransferase (Hprt) -/-, PE-selectin -/-, Winnie (Muc2 single nucleotide mutation) or RaW (cross Winnie /Rag1 -/-) male or female C57Bl/6 mice, were gavaged daily with 100µL of tap water (vehicle control) or drugs in the same volume of water for periods up to 28 days. The administered drugs were 6TG (0-5 mg/kg/d) or 6MP, methyl-6MP or methyl-6TG (≤ 5 mg/kg/d). Furthermore, 6TG effects were also characterised in vivo in different haematopoietic organs and in vitro on hepatic and endothelial cell lines. The safe administration of 6TG in IBD patients would translate into a huge therapeutic value, providing both a faster onset of action and an efficacious treatment