Kemena A, Gandhi V, Shewach D S, Keating M, Plunkett W
University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cancer Chemother Pharmacol. 1992;31(3):193-9. doi: 10.1007/BF00685547.
The active 5'-triphosphate of arabinosyl-2-fluoroadenine (F-ara-ATP) increases the anabolism of arabinosylcytosine (ara-C), whereas ara-C 5'-triphosphate inhibits the phosphorylation of arabinosyl-2-fluoroadenine (F-ara-A) in human leukemia cells in vitro. These interactions have a potential impact on drug scheduling. Clinical trials of relapsed leukemia in which fludarabine (F-ara-A 5'-monophosphate) and ara-C were given in sequence provided the opportunity to evaluate the effects of ara-C infusion on two sequelae: the pharmacokinetics of F-ara-A in plasma and that of F-ara-ATP in leukemia cells. First, F-ara-A pharmacokinetics were altered by ara-C infusion. This was visualized as a transient increase in F-ara-A plasma levels during the ara-C infusion that was given 4 h after fludarabine. The perturbation in F-ara-A plasma levels was dependent on the dose ara-C. Second, peak F-ara-ATP concentrations were lower in leukemia cells of patients who received ara-C in addition to fludarabine as compared with those who received fludarabine alone. The terminal half-life of F-ara-A in plasma and the half-life of intracellular F-ara-ATP were reduced after the ara-C infusion in a concentration-dependent manner. Studies using purified deoxycytidine kinase support the conclusion that the increase in plasma levels of F-ara-A is in part the result of an effective competition by ara-C for phosphorylation by this enzyme, leading to a perturbation of the pharmacokinetics of intracellular F-ara-ATP.
阿拉伯糖基-2-氟腺嘌呤的活性5'-三磷酸酯（F-ara-ATP）可增加阿糖胞苷（ara-C）的合成代谢，而阿糖胞苷5'-三磷酸酯在体外可抑制人白血病细胞中阿拉伯糖基-2-氟腺嘌呤（F-ara-A）的磷酸化。这些相互作用对药物给药方案具有潜在影响。在复发性白血病的临床试验中，先后给予氟达拉滨（F-ara-A 5'-单磷酸酯）和阿糖胞苷，这为评估阿糖胞苷输注对两个后续效应的影响提供了机会：血浆中F-ara-A的药代动力学以及白血病细胞中F-ara-ATP的药代动力学。首先，阿糖胞苷输注改变了F-ara-A的药代动力学。这表现为在氟达拉滨给药4小时后进行阿糖胞苷输注期间，F-ara-A血浆水平短暂升高。F-ara-A血浆水平的扰动取决于阿糖胞苷的剂量。其次，与仅接受氟达拉滨的患者相比，除氟达拉滨外还接受阿糖胞苷的患者白血病细胞中F-ara-ATP的峰值浓度较低。阿糖胞苷输注后，血浆中F-ara-A的终末半衰期和细胞内F-ara-ATP的半衰期以浓度依赖的方式缩短。使用纯化的脱氧胞苷激酶进行的研究支持以下结论：F-ara-A血浆水平的升高部分是由于阿糖胞苷与该酶的磷酸化发生有效竞争，导致细胞内F-ara-ATP药代动力学受到扰动。
