Hiddemann W, Schleyer E, Unterhalt M, Zühlsdorf M, Rolf C, Reuter C, Kewer U, Uhrmeister C, Wörmann B, Büchner T
Department of Hematology, University of Göttingen, Germany.
Leukemia. 1992 Dec;6(12):1273-80.
The increasing insights into the pharmacokinetics and the metabolism of cytosine arabinoside (AraC) have improved the rationale for its application in leukemia therapy and have led to a pharmacologically directed design of antileukemic treatment. The current study aims at adding to this approach by detecting differences in the intracellular metabolism of AraC 5'-triphosphate (AraCTP) between leukemic and normal mononuclear blood cells. Measurements of intracellular AraCTP levels were complemented by determinations of plasma AraC and AraU concentrations and were performed in 32 patients with acute myeloid leukemia undergoing combination therapy including either conventional (100 mg/m2 daily) or high-dose (1.0 or 3.0 g/m2 twice daily) AraC. Plasma AraC concentration showed a linear relationship to the applied AraC dose but did not correlate with intracellular AraCTP levels. During conventional-dose AraC therapy little interpatient variation was observed in AraCTP retention times in leukemic blasts from 5 patients with t1/2 values ranging from 1.70 to 2.50 h (median 2.14 h). In all cases AraCTP levels declined rapidly after the end of the AraC infusion. Substantial differences in AraCTP retention times were revealed, however, during 3 h infusions of either 1.0 or 3.0 g/m2 AraC in leukemic blasts from 10 patients with t1/2 values between 1.60 to 7.63 h (median 2.42 h). In addition, AraCTP levels declined in only one patient by > 10% within the first hour after the end of therapy and remained constant or even increased up to 1.5-fold in a post-treatment period of 1 to 2.5 h in the other nine cases. In contrast, AraCTP retention times were relatively uniform in normal mononuclear blood cells from 11 patients with t1/2 values of 3.34 to 5.29 h (median 3.85 h). More importantly, AraCTP levels dropped by > 10% within the first hour after the end of the high-dose AraC infusion in eight of 11 cases. A post-therapeutic increase > 10% was not observed in any patient. Similar findings emerged after in vitro exposure of normal bone marrow cells from six healthy volunteers to 20 mumol/l AraC for 3 h revealing a > 10% decrease of intracellular AraCTP within the first post-treatment hour in all cases with AraCTP retention times of 2.29 to 8.63 h (median 3.20 h). These differences in AraCTP pharmacokinetics between leukemic and normal blood cells may provide the basis for a modified timing of AraC administration with the aim of selectively maintaining cytotoxic AraCTP levels in leukemic blasts while allowing an intermittent drop of AraCTP levels in normal cells.(ABSTRACT TRUNCATED AT 400 WORDS)
对阿糖胞苷（AraC）药代动力学和代谢的深入了解，为其在白血病治疗中的应用提供了更合理的依据，并促成了抗白血病治疗的药理学导向设计。本研究旨在通过检测白血病和正常单核血细胞中阿糖胞苷5'-三磷酸（AraCTP）细胞内代谢的差异，来补充这一方法。通过测定血浆阿糖胞苷和阿糖尿苷浓度，对细胞内AraCTP水平进行补充测量，并在32例接受联合治疗的急性髓性白血病患者中进行，联合治疗包括常规（每日100mg/m²）或高剂量（每日两次，每次1.0或3.0g/m²）阿糖胞苷。血浆阿糖胞苷浓度与所用阿糖胞苷剂量呈线性关系，但与细胞内AraCTP水平无关。在常规剂量阿糖胞苷治疗期间，5例患者白血病原始细胞中AraCTP保留时间的患者间差异较小，t1/2值范围为1.70至2.50小时（中位数2.14小时）。在所有情况下，阿糖胞苷输注结束后，AraCTP水平迅速下降。然而，在10例患者的白血病原始细胞中，在3小时输注1.0或3.0g/m²阿糖胞苷期间，发现AraCTP保留时间存在显著差异，t1/2值在1.60至7.63小时之间（中位数2.42小时）。此外，治疗结束后第一小时内，只有1例患者的AraCTP水平下降超过10%，在其他9例患者中，在治疗后1至2.5小时内，AraCTP水平保持恒定甚至增加至1.5倍。相比之下，11例患者正常单核血细胞中AraCTP保留时间相对均匀，t1/2值为3.34至5.29小时（中位数3.85小时）。更重要的是，11例中有8例在高剂量阿糖胞苷输注结束后的第一小时内，AraCTP水平下降超过10%。在任何患者中均未观察到治疗后增加超过10%的情况。在6名健康志愿者的正常骨髓细胞体外暴露于20μmol/L阿糖胞苷3小时后，也出现了类似的结果，所有病例中细胞内AraCTP在治疗后第一小时内下降超过10%，AraCTP保留时间为2.29至8.63小时（中位数3.20小时）。白血病和正常血细胞之间AraCTP药代动力学的这些差异，可能为调整阿糖胞苷给药时间提供依据，目的是在白血病原始细胞中选择性维持细胞毒性AraCTP水平，同时允许正常细胞中AraCTP水平间歇性下降。（摘要截断于400字）
