Cerebrospinal Fluid and Plasma Pharmacokinetics of High Doses of 1-β-d-Arabinofuranosylcytosine in Nonhuman Primates¹

The pharmacokinetics of 1-β-d-arabinofuranosylcytosine (ara-C) in plasma, cerebrospinal fluid (CSF), and urine was studied in nonhuman primates. Conventional and high-dose schedules of ara-C were administered i.v. and intraventricularly through indwelling Ommaya reservoirs. ara-C and its metabolite 1-β-d-arabinofuranosyluracil (ara-U) were measured by high-pressure liquid chromatography.

Due to rapid peripheral deamination (230 nm ara-C/hr/ml plasma), the half-life of ara-C in plasma after a 140-mg/kg i.v. 1-hr infusion was short (3.7 min). Peak plasma concentrations of ara-C, ranging between <0.1 and 49 µg/ml, were dose dependent (ara-C, 15 to 140 mg/kg). Under these conditions, ara-C was undetectable in CSF. About 53% of the administered dose (140 mg/kg) was excreted in urine during the first 5 hr mostly as ara-U.

Intraventricular administration of 50 and 250 mg of ara-C resulted in peak lumbar CSF levels of 435 and 2235 µg/ml, respectively, at about 155 and 80 min postinjection. Concomitant ara-U levels were one-tenth of those of ara-C and increased progressively, suggesting deamination of the drug in the central nervous system. 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 µg/ml at about 180 min with a prolonged clearance. Concomitant plasma levels throughout the study were less than 0.1 µg/ml, suggesting slower equilibrium. No hematological or nervous system toxicity was observed during these studies. The clinical implications of these findings are discussed.