Plasma and cerebrospinal fluid pharmacokinetics of 1-beta-D-arabinofuranosylcytosine and 1-beta-D-arabinofuranosyluracil following the repeated intravenous administration of high- and intermediate-dose 1-beta-D-arabinofuranosylcytosine.
We examined the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) and 1-beta-D-arabinofuranosyluracil (ara-U) in 19 patients with acute leukemia in order to determine whether ara-C or ara-U accumulate in these fluid compartments over time. Plasma and CSF samples were obtained just prior to the conclusion of the first and seventh, and immediately before the second and eighth, 2-h, twice-daily i.v. infusions of 3 g/m2/dose of ara-C (n = 10), 2 g/m2/dose of ara-C (n = 3), and 0.75 g/m2/dose of ara-C (n = 6). There was no accumulation of ara-C in the plasma or CSF, or of ara-U in the plasma following repeated ara-C infusions, ara-U did accumulate in the CSF; the end-dose 1/end-dose 7 CSF ara-U ratio was 0.35 +/- 0.12 and significantly different from this ratio for CSF ara-C (2.10 +/- 3.01; P = 0.004). The end-dose 7 CSF ara-U level was greater than the end-dose 1 CSF ara-U level in all paired specimens. There was a significant correlation between the dose of ara-C administered and the end-dose plasma ara-C and the end-dose CSF ara-U levels (P less than 0.02). One patient who received 3 g/m2/dose of ara-C developed neurotoxicity; his plasma and CSF ara-C and ara-U levels were not extraordinary during the period of ara-C administration, but he had persistent CSF ara-U demonstrable 75 h after his final ara-C dose. CSF ara-U accumulation might underlie the pathophysiology of ara-C-induced neurotoxicity. Intermediate doses of ara-C given i.v. (0.75 g/m2/dose over 2 h) appeared to generate therapeutic CSF ara-C levels and cleared CSF leukemia in one patient.
Damon
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Cancer Research Institute, University of California, San Francisco 94143.
Plunkett
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Linker
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CA
D000328:Adult; D001086:Arabinofuranosyluracil / Q000097:blood* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D003561:Cytarabine / Q000097:blood* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000134:cerebrospinal fluid / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000134:cerebrospinal fluid / Q000188:drug therapy; D012044:Regression Analysis
D003561:Cytarabine; D001086:Arabinofuranosyluracil