Optimizing therapy with 6-mercaptopurine and azathioprine: to measure or not to measure?

Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

“…In the early 2000s, several studies proposed a therapeutic threshold ranging from 230 to 260 pmol/8 × 10 8 RBCs . Based on this threshold, several recent clinical guidelines have advocated determining 6‐TGN levels with 6‐MMPR in patients on AZA or MP to maximise therapeutic response and to minimise adverse effects by detecting poor compliance to treatment, underdosing of thiopurines, pharmacological resistance to thiopurines, preferential 6‐MMP metabolism, and overdose or refractoriness to thiopurines (Table ) . However, from an evidence‐based perspective, these recommendations are still premature, especially with respect to the cut‐off value between therapeutic response and adverse effects.…”

“…The proposed threshold cut‐off value of 6‐MMPR for hepatotoxicity is 5700 pmol/8 × 10 8 RBCs . Several recent clinical guidelines have advocated determining 6‐MMPR levels in patients on AZA or MP for avoiding hepatotoxicity . However, this cut‐off value of 6‐MMPR cannot practically serve as a complete guide for the dosing of AZA or MP in the treatment of IBD for prediction and avoidance of adverse effects.…”

“…Preferential 6‐MMP metabolism is characterised by higher 6‐MMP levels without an increase in therapeutic 6‐TGN levels after dose escalation of thiopurines. This phenomenon is associated with a lack of therapeutic response, and more adverse events including hepatotoxicity (Table ) . Allopurinol is a XO inhibitor used in doses up to 800 mg daily to decreases uric acid production .…”

Update 2014

“…16 After conversion into 6-MP, there are 3 different metabolic pathways; competition and variation in shift among these pathways can increase and decrease metabolite levels, respectively. 17,22,23 Other proposed mechanisms of action include inhibition of several immune-and inflammationrelated genes. The third pathway involves conversion to the therapeutic 6-TGN by multiple enzymes, including hypoxanthine phosphoribosyltransferase (HPRT), TPMT, inosine monophosphate dehydrogenase (IMPDH), and guanosine monophosphate synthetase (GMPS).…”

“…1,[6][7][8][9][10][11][12][13][14][15]17,18,[21][22][23][24][25][27][28][29][30][31] This dosing strategy is based on the fact that 6-MP comprises 55% of AZA in molecular weight, and about 88% of AZA is ultimately converted to 6-MP. 1,[6][7][8][9][10][11][12][13][14][15]17,18,[21][22][23][24][25][27][28][29][30][31] This dosing strategy is based on the fact that 6-MP comprises 55% of AZA in molecular weight, and about 88% of AZA is ultimately converted to 6-MP.…”