HEPATOTOXICITY OF 6-MERCAPTOPURINE IN CHILDHOOD ACUTE LYMPHOCYTIC-LEUKEMIA - PHARMACOKINETIC CHARACTERISTICS

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastr ointestinal (GI) and hepatic effects. Four patients, ages 6.9 +/- 2.6 (mean +/- S.D.) years, with acute lymphocytic leukemia (ALL) on mainte nance chemotherapy including 6MP, developed nausea, vomiting, abdomina l pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 +/- 1 .0 (range 0.5-2) years. Liver biopsy in 1 patient was suggestive of dr ug-induced intrahepatic cholestatis. Symptoms resolved and liver funct ion returned to normal after discontinuation of 6MP. Pharmacokinetic d ata of the symptomatic patients were compared with those of 25 ALL pat ients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabol ites of 6MP in red blood cells of the patients with hepatotoxicity, we re not significantly different when compared to patients without hepat otoxicity, suggesting similar absorption of 6MP in both groups. Time t o achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak level s and standardized concentration versus time curve (AUG) per 1 mg of 6 MP per m(2) of body surface area were significantly lower in the patie nts with hepatotoxicity (P = 0.016; P = 0.037, respectively). A signif icant correlation between peak 6MP levels and standardized AUC (r = 0. 729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, lea ding to hepatotoxicity. (C) 1996 Wiley-Liss, Inc.