6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity.
BACKGROUND
6-Mercaptopurine (6-MP) has confirmed short and longterm efficacy in the treatment of IBD. However, the relation between its metabolism, efficacy, and side effects is not well understood.


OBJECTIVE
To assay 6-MP metabolites and to correlate levels with drug compliance, disease activity, and adverse effects of treatment.


METHODS
Heparinised blood was obtained prior to daily administration of 6-MP in 25 adolescent 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.


METHODS
Erythrocyte free bases 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP) were measured (pmol/8 x 10(8) red blood cells) using reverse phase high performance liquid chromatography.


RESULTS
Disease activity (modified Harvey-Bradshaw index) improved significantly with 6-MP (p = 0.001). Clinical remission was achieved in 72% of patients, who stopped taking prednisone, or were successfully weaned to a low alternate day dose (< 0.4 mg/kg/OD). Remission correlated well with erythrocyte 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 metabolite levels. One patient refractory to 6-MP had 6-TG, but no measureable 6-MMP production, suggesting deficient thiopurine methyl-transferase 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 performance liquid chromatography measurement of erythrocyte 6-MP metabolites may provide a quantitative assessment of patient responsiveness and compliance to treatment. The data support an immunosuppressive role for 6-TG, and potential cytotoxicity of raised 6-MMP levels.
Cuffari
C
C
Department of Pediatrics, Université de Montréal, Canada.
Théorêt
Y
Y
Latour
S
S
Seidman
G
G
D000293:Adolescent; D000328:Adult; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000627:therapeutic use*; D015122:Mercaptopurine / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use*; D010349:Patient Compliance; D013866:Thioguanine / Q000097:blood; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D013866:Thioguanine