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Plasma and Cerebrospinal Fluid Pharmacokinetics of 1-ß-D-Arabinofuranosylcytosine and 1-ß-D-Arabinofuranosyluracil following the Repeated Intravenous Administration of High- and Intermediate-Dose 1-ß-D-Arabinofuranosylcytosine¹

Cancer Research Institute, University of California, San Francisco, California 94143 [L. E. D., C. A. L.] and the University of Texas, M. D. Anderson Cancer Center, Department of Medical Oncology, Houston, Texas 77030 [W. P.]

We examined the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 1-ß-D-arabinofuranosylcytosine (ara-C) and 1-ß-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 = 0.04). 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 < 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.

¹ Supported by a grant from the Upjohn Co., Kalamazoo, MI, and Grant CA 32839 from the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Cancer Research Institute, M-1282, University of California, San Francisco, CA 94143-0128.

Received 2/25/91. Accepted 6/ 4/91.

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