CEREBROSPINAL-FLUID AND PLASMA PHARMACOKINETICS OF HIGH-DOSES OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE IN NON-HUMAN PRIMATES

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (11) , 5190-5193
Abstract
The pharmacokinetics of 1-.beta.-D-arabinofuranosylcytosine (ara-C) in plasma, CSF and urine was studied in nonhuman primates (Papio anubis and Macaca mulatta). Conventional and high-dose schedules of ara-C were administered i.v. and intraventricularly through indwelling Ommaya reservoirs. ara-C and its metabolite 1-.beta.-D-arabinofuranosyluracil (ara-U) were measured by high-pressure liquid chromatography. Due to rapid peripheral deamination, the half-life of ara-C in plasma after a 140 mg/kg i.v. 1 h infusion was 3.7 min. Peak plasma concentrations of ara-C were dose dependent. ara-C was undetectable in CSF. About 53% of the administered dose (140 mg/kg) was excreted in urine during the first 5 h mostly as ara-U. Intraventricular administration of 50 and 250 mg of ara-C resulted in peak lumbar CSF levels of 435 and 2235 .mu.g/ml, respectively, at about 155 and 80 min postinjection. Concomitant ara-U levels were 1/10 of those of ara-C and increased progressively, suggesting deamination in the CNS. The half-life of ara-C in CSF ranged between 50 and 60 min. Administration of 50 mg of ara-U intraventricularly resulted in peak lumbar ara-U levels of 595 .mu.g/ml at about 180 min with a prolonged clearance. Concomitant plasma levels throughout the study were < 0.1 .mu.g/ml, suggesting slower equilibrium. No hematological or nervous system toxicity was observed during these studies. The clinical implications of these findings are discussed. [ara-C is active against acute leukemia.].

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