PHARMACOKINETICS AND METABOLISM OF THIOPURINES IN CHILDREN WITH ACUTELYMPHOBLASTIC-LEUKEMIA RECEIVING 6-THIOGUANINE VERSUS 6-MERCAPTOPURINE

Mercaptopurine(6MP) has been the standard drug for maintenance therapy of acute lymphoblastic leukemia. In a multicenter study we investigat ed whether thioguanine (6TG), which is converted more directly to the cytotoxic thioguanine nucleotides (TGN), offers a therapeutic advantag e over 6MP. In this study (CO-ALL-92), 6TG was randomized versus 6MP i n maintenance therapy, whereby the doses of both drugs had to be adjus ted to a white blood cell (WBC) count of between 2 and 3/nl. In 19 chi ldren the plasma levels of both drugs and/or the accumulation of their metabolites in red blood cells (RBC) were measured during intensive t reatment in two consecutive chemotherapy blocks, and in 54 children th e metabolites in RBC were measured every 3 months during daily treatme nt in maintenance therapy. There was a marked interindividual differen ce in the plasma kinetics of the two drugs; after identical doses of 1 00 mg/m(2) an about 4-fold higher peak concentration of the parent dru g was reached with 6MP. The main metabolites of 6TG were thioguanine n ucleotides (TGN), whereas during 6MP treatment, methylated thioinosine nucleotides (TIN) predominated in erythrocytes. In patients receiving 6TG during maintenance therapy (22 patients) the concentration of met hylated TGN reached about 40% of that of unmethylated TGN; after 6MP a dministration (32 patients) the methylated TIN were concentrated about 26-fold higher in RBC than were TGN. In contrast to 6TG, for 6MP the pattern of metabolites shifted toward the methylated ones with increas ing dose. The median TGN concentration was about 7-fold higher in the TG branch, although the median dose was only about 70% of that of 6MP. The WBC values were equivalent in the two treatment groups. Our resul ts suggest that the cytotoxic effect of 6MP is not based solely on the formation of TGN.