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spectively. The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ARA-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to form uric acid. Ring opening of uric acid is followed by further oxidation results in the formation of allantoin. Nelarabine and ARA-G are rapidly eliminated from the plasma with a half-life of approximately 30 minutes and 3 hours, respectively, after a 1500 mg/m2 adult nelarabine dose. Plasma ARA-G Cmax values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ARA-G. The AUC of ARA-G is 37-times higher than that for nelarabine on day 1 after nelarabine 1500 mg/m2 IV dose (162 +/- 49 mcg.h/ml vs 4.4 +/- 2.2 mcg.h/ml, respectively). After a nelarabine adult dose of 1500 mg/m2, a mean intracellular Cmax for ARA-GTP appeared within 3 to 25 hours on day 1. Exposure (AUC) to intracellular ARA-GTP was 532-times higher than that for nelarabine and 14-times higher than that for ARA-G (2339 +/- 2628 mcg.h/ml vs 4.4 +/- 2.2 mcg.h/ml and 162 +/- 49 mcg.h/ml, respectively). Because the intracellular levels of ARA-G were so prolonged, its elimination half-life could not be accurately determined. Nelarabine and ARA-G are partially eliminated by the kidneys. Mean urinary excretion of nelarabine and ARA-G was 6.6 +/- 4.7% and 27 +/- 15% of the administered dose, respectively in adult patients over 24 hours. |
