immunosuppressive effect of thiopurine drugs is mediated
primarily by the cytotoxic metabolite, 6TGN, and
incorporation of these false bases into DNA. Accumulation of
high levels of 6TGN is also responsible for some side
effects of thiopurine drugs, and has been associated with
leucopenia. Furthermore, high levels of the inactive
metabolite 6MMPN, which is formed via the
TPMT pathway, may be associated with hepatotoxicity.
Indications for measuring thiopurine metabolites include
suspected non-compliance or treatment with a suboptimal dose
or failure to respond to standard doses of thiopurine drugs.
Measurement of 6MMPN helps to distinguish patients who are
under-dosed or non-compliant (6MMPN levels appropriately
low) from those demonstrating resistance to thiopurine
drugs, i.e., preferentially metabolising thiopurine drugs to
inactive 6MMPN rather than 6TGN (6MMPN disproportionately
increased). In resistant patients, increasing the
azathioprine dose is not helpful and further increases 6MMPN
levels, predisposing to hepatotoxicity.