PHARMACOKINETICS OF N-4-BEHENOYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE IN PATIENTS WITH ACUTE-LEUKEMIA

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (7) , 3412-3416
Abstract
N4-Behenoyl-1-.beta.-D-arabinofuranosylcytosine (BHAC), a lipophilic and deaminase-resistant derivative of 1-.beta.-D-arabinofuranosylcytosine (ara-C), was studied pharmacologically in patients with acute leukemia. The concentrations of BHAC, ara-C, and 1-.beta.-D-arabinofuranosyluracil (ara-U) were measured by high-performance liquid chromatography, bioassay, and gas chromatography-mass spectrometry-mass fragmentography, respectively. The data of plasma BHAC concentrations were analyzed by a MULTI computer program. In 7 patients given BHAC (200 mg/body wt; 2.97 to 4.26 mg/kg) i.v. for 90 min, the plasma disappearance curve of BHAC was biphasic with a mean initial half-life of 0.37 h and a mean 2nd half-life of 5.27 h. The apparent volume of the central compartment and the apparent volume of distribution were 0.047 and 0.316 l/kg, respectively; the systemic clearance was 0.051 l/h per kg. BHAC concentrations in erythrocytes were significantly higher (P < 0.01) than those in plasma at 4 to 22.5 h after infusion, suggesting that the erythrocytes may act as a reservoir for the drug. The plasma ara-U level increased to 603 ng/ml at 4 h after infusion, and it was > 129 ng/ml for at least 22.5 h after infusion. Plasma ara-C levels, which could be detected in only 2 of 11 patients examined, were maintained (> 0.08 .mu.g/ml) for 8 h after infusion. Urinary BHAC excretion was < 0.2 .mu.g/ml of the sensitivity limit in all samples. Prologed urinary ara-C excretion was detected, but it was only 0.5% of the administered BHAC for 24 h. At 12 h after a 200-mg infusion of BHAC, BHAC level in bone marrow fluid was significantly higher (P < 0.01) than that in plasma. In spite of the lipophilic nature of the agent, the BHAC concentration in CSF was < 0.2 .mu.g/ml in 8 of 9 patients without meningeal involvement. These findings were thought to indicate a restricted and prolonged BHAC distribution including plasma, blood cells, and bone marrow fluids, which may be of importance in the administration of BHAC in the chemotherapy of hematological cancers.

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