6-MERCAPTOPURINE METABOLISM IN CROHNS-DISEASE - CORRELATION WITH EFFICACY AND TOXICITY

Background-6-Mercaptopurine (6-MP) has confirmed short and longterm ef ficacy in the treatment of IBD. However, the relation between its meta bolism, efficacy, and side effects is not well understood. Aims-To ass ay 6-MP metabolites and to correlate levels with drug compliance, dise ase activity, and adverse effects of treatment. Patients-Heparinised b lood was obtained prior to daily administration of 6-MP in 25 adolesce nt Crohn's disease patients (14 ileocolitis, 11 colitis) receiving 1.2 (range 0.4-1.6) mg/kg/day for a mean of 17 (range 4-65) months. Metho ds-Erythrocyte free bases 6-thioguanine (6-TG) and 6-methyl-mercaptopu rine (6-MMP) were measured (pmol/ 8 x 10(8) red blood cells) using rev erse phase high performance liquid chromatography. Results-Disease act ivity (modified Harvey-Bradshaw index) improved significantly with 6-M P (p=0.001). Clinical remission was achieved in 72% of patients, who s topped taking prednisone, or were successfully weaned to a low alterna te day dose (<0.4 mg/kg/OD). Remission correlated well with erythrocyt e 6-TG (p<0.05), but not 6-MMP levels. Neutropenia was associated with 6-MP use (p<0.005), but did not correlate with erythrocyte 6-MP metab olite levels. One patient refractory to 6-MP had 6-TG, but no measurea ble 6-MMP production, suggesting deficient thiopurine methyl-transfera se activity or poor compliance. 6-MP induced complications (hepatitis, pancreatitis, and marrow suppression) were generally associated with increased 6-MMP levels. Conclusions-These results suggest that high pe rformance liquid chromatography measurement of erythrocyte 6-MP metabo lites may provide a quantitative assessment of patient responsiveness and compliance to treatment. The data support an immunosuppressive rol e for 6-TG, and potential cytotoxicity of raised 6-MMP levels.