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Pharmacologic and Clinical Studies of N4-Behenoyl-1-Beta-D-Arabinofuranosylcytosine

  • Kazumasa Yamada
  • Kohei Kawashima
  • Yukio Kato
  • Yasuo Morishima
  • Mitsune Tanimoto
  • Ryuzo Ohno
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 70)

Summary

Two metabolites of N4-behenoyl-1-β-D-arabinofuranosylcytosine (BH-AC) were found in the plasma and urine, and a hydrolytic product, arabinosylcytosine (ara-C) and its deaminated product, arabinosyluraci (ara-U), were found in a preclinical study using monkeys. Of a given dose, 96% was found as ara-U and 3% as ara-C in urine in 24 h. The plasma disappearance curve of BH-AC is biphasic; the half-life of the initial phase is 40 min and that of the second phase is 120 min. At 8 h the BH-AC level is 21.9 μg/ml and falls exponentially to 3.6 μg/ml by 12 h. Ara-C was detected at the levels of 0.4–0.6 μg/ml for 4 h. Comparative data of pharmacokinetic parameters among BH-AC, ara-C, and O2,2′-cyclocytidine showed that BH-AC had the longest plasma half-life, the smallest elimination-rate constant and the smallest excretion-rate constant. The plasma-clearance study of BH-AC in 13 patients showed essentially a pattern similar to that in monkeys; the plasma t1/2 of 60 min in the first phase and of 180 min in the second. The BH-AC level at 2 h is 15.4 μg/ml, and 1.8 μg/ml at 8 h.

Initial phase I study of BH-AC was evaluated in 14 patients with leukemia and other malignancies. The starting dose was 1.5 mg/kg given as a single IV infusion for 3. The doses were then escalated up to 5.0 mg/kg. No side effects were noted with a single dose schedule. Daily consecutive infusions of 2.0 mg/kg–6.0 mg/kg for 4–21 days resulted in two patients having nausea, two anorexia, and one developing skin eruptions. Significant hematologic effects were noted with the daily infusion. One patient with acute myeloblasts leukemia achieved complete remission with 5.0 mg/kg BH-AC given daily for 21 days.

Its pharmacologic features, minimal toxicity, and the capability of inducing complete remission in acute leukemia indicate that BH-AC undoubtedly deserves further prospective clinical trials.

Keywords

Acute Lymphoblastic Leukemia Acute Leukemia Cytosine Arabinoside Acute Myeloblastic Leukemia Urinary Excretion Data 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1980

Authors and Affiliations

  • Kazumasa Yamada
    • 1
  • Kohei Kawashima
    • 1
  • Yukio Kato
    • 1
  • Yasuo Morishima
    • 1
  • Mitsune Tanimoto
    • 1
  • Ryuzo Ohno
    • 1
  1. 1.First Department of Internal MedicineNagoya University School of MedicineShowa-ku, NagoyaJapan

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