Pharmacological studies of 5′-esters of 1-β-d-arabinofuranosylcytosine (ara-C) were performed in three species (mouse, pig, and man). In mice, after a single i.p. injection of a suspension of tritiated 1-β-d-arabinofuranosylcytosine 5′-palmitate (PalmO-ara-C) at a therapeutic dose of 150 mg/kg, 30% of the administered radioactivity was recovered in the urine in 24 hr and 56% was recovered after 7 days. Excretion was less rapid after s.c. administration, ara-C and 1-β-d-arabinofuranosyluracil each accounted for about 50% of the excreted radioactivity, and no PalmO-ara-C was found. Plasma ara-C concentrations of greater than 0.1 µg/ml were detected 24 hr after i.p. administration of PalmO-ara-C (150 mg/kg). Single doses of PalmO-ara-C were effective against L1210 leukemic mice when administered 5 to 7 days before tumor inoculation. In a pig, after i.m. injection of tritiated PalmO-ara-C (60 mg/kg, two sites), only 7% of the administered radioactivity was recovered in the urine over a 1-week period. Similar low rates of excretion were also observed in patients treated i.m. with PalmO-ara-C or 1-β-d-arabinofuranosylcytosine 5′-benzoate. No ara-C was detected in the plasma, which is consistent with the absence of clinical toxicity or myelosuppression in Phase 1 trials of PalmO-ara-C at doses up to 1500 mg/sq m every 3 weeks for as many as eight courses.

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Supported in part by Contracts N01-CM-53773 and N01-CM-33707, Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education and Welfare.

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