Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease

Background & Aims: The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopu rine (6-MMP) nucleotide metabolites, the latter genetically controlled by t hiopurine methyltransferase (TPMT), We sought to determine optimal therapeu tic 6-MP metabolite levels and their correlation with medication-induced to xicity and TPMT genotype, Methods: Therapeutic response was determined in 9 2 pediatric patients with inflammatory bowel disease coincidentally with he matologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype, Results: Clinical respons e was highly correlated with 6-TG levels (P < 0.0001) but not with any othe r variable, including 6-MMP levels, drug dose, gender, and concurrent medic ations. The frequency of therapeutic response increased at 6-TG levels > 23 5 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with e levated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Althoug h leukopenia was associated with higher 6-TG levels (P < 0.03), it was obse rved in only 8% of responders. Patients heterozygous for TPMT (8/92) had hi gher 6-TG levels (P < 0.0001), and all responded to therapy. Conclusions: 6 -MP metabolite levels and TPMT genotyping may assist clinicians in optimizi ng therapeutic response to 6-MP and identifying individuals at increased ri sk for drug-induced toxicity.