TY - JOUR
T1 - Saturation of 1 -β-arabinofuranosylcytosine 5'-triphosphate accumulation in leukemia cells during high-dose l-β-d-arabinofuranosylcytosine therapy 1
AU - Plunkett, W.
AU - Liliemark, J. O.
AU - Adams, T. M.
AU - Nowak, B.
AU - Estey, E.
AU - Keating, M. J.
AU - Keating, M. J.
PY - 1987/6
Y1 - 1987/6
N2 - Twenty-seven patients with refractory leukemia were treated with 1-β-D-arabinofuranosylcytosine (ara-C), 0.3 to 3.0 g/m2as i.v. infusions over 1, 2, 4, or 24 h. The pharmacokinetics of ara-C in plasma and its 5'-triphosphate (ara-CTP) in leukemic cells from peripheral blood were studied after a single infusion of 3 g/m2over 2 h in 13 patients. Accumulation of ara-CTP in leukemic cells remained linear until 1 to 2 h after the infusion. At the time when the rate of ara-CTP accumulation deviated from linearity, the plasma concentration of ara-C was 5-to 20-fold lower [8.1 ± 4.4 (SD) μM] than the steady-state level during the infusion. Plasma ara-C and cellular ara-CTP pharmacokinetics were studied after two serial infusions in 14 additional patients. Varying the duration of infusion of an ara-C dose between 1, 2, and 4 h (corresponding to infusion rates of 3000, 1500, and 750 mg/m2/h) did not substantially change the rate of ara-CTP accumulation by leukemic cells. The peak ara-CTP concentration and the area under the concentration times time curve (AUC) of ara-CTP in leukemic cells increased with prolongation of the infusion. Although steady-state concentration of ara-C and AUC of ara-C in plasma were proportionally reduced by 1.0 or 0.5 g/m2infusion over 2 h, ara-CTP accumulation rate and AUC in leukemic cells did not change compared with administration of 3 g/m2over 2 h. However, when the infusion rate was further reduced to 0.4 or 0.3 g/m2over 2 h, resulting in steady-state plasma ara-C concentrations of less than 7 μM, the accumulation rate of ara-CTP was substantially reduced as was the ara-CTP intracellular AUC. The cellular elimination rate of ara-CTP remained constant under all infusion conditions. These findings support the conclusion that high-dose ara-C therapy, as currently administered, results in plasma ara-C concentrations that saturate the accumulation of ara-CTP by circulating leukemic cells. We recommend that intermediate dose rates, 200 to 250 mg/m2/h, be evaluated in future studies as an alternative to the substantially higher ara-C dose rates currently in use.
AB - Twenty-seven patients with refractory leukemia were treated with 1-β-D-arabinofuranosylcytosine (ara-C), 0.3 to 3.0 g/m2as i.v. infusions over 1, 2, 4, or 24 h. The pharmacokinetics of ara-C in plasma and its 5'-triphosphate (ara-CTP) in leukemic cells from peripheral blood were studied after a single infusion of 3 g/m2over 2 h in 13 patients. Accumulation of ara-CTP in leukemic cells remained linear until 1 to 2 h after the infusion. At the time when the rate of ara-CTP accumulation deviated from linearity, the plasma concentration of ara-C was 5-to 20-fold lower [8.1 ± 4.4 (SD) μM] than the steady-state level during the infusion. Plasma ara-C and cellular ara-CTP pharmacokinetics were studied after two serial infusions in 14 additional patients. Varying the duration of infusion of an ara-C dose between 1, 2, and 4 h (corresponding to infusion rates of 3000, 1500, and 750 mg/m2/h) did not substantially change the rate of ara-CTP accumulation by leukemic cells. The peak ara-CTP concentration and the area under the concentration times time curve (AUC) of ara-CTP in leukemic cells increased with prolongation of the infusion. Although steady-state concentration of ara-C and AUC of ara-C in plasma were proportionally reduced by 1.0 or 0.5 g/m2infusion over 2 h, ara-CTP accumulation rate and AUC in leukemic cells did not change compared with administration of 3 g/m2over 2 h. However, when the infusion rate was further reduced to 0.4 or 0.3 g/m2over 2 h, resulting in steady-state plasma ara-C concentrations of less than 7 μM, the accumulation rate of ara-CTP was substantially reduced as was the ara-CTP intracellular AUC. The cellular elimination rate of ara-CTP remained constant under all infusion conditions. These findings support the conclusion that high-dose ara-C therapy, as currently administered, results in plasma ara-C concentrations that saturate the accumulation of ara-CTP by circulating leukemic cells. We recommend that intermediate dose rates, 200 to 250 mg/m2/h, be evaluated in future studies as an alternative to the substantially higher ara-C dose rates currently in use.
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M3 - Article
C2 - 3471322
AN - SCOPUS:0023273525
SN - 0008-5472
VL - 47
SP - 3005
EP - 3011
JO - Cancer Research
JF - Cancer Research
IS - 11
ER -