Plunkett W, Liliemark J O, Adams T M, Nowak B, Estey E, Kantarjian H, Keating M J
Cancer Res. 1987 Jun 1;47(11):3005-11.
Twenty-seven patients with refractory leukemia were treated with 1-beta-D-arabinofuranosylcytosine (ara-C), 0.3 to 3.0 g/m2 as 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/m2 over 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) microM] 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/m2 infusion over 2 h, ara-CTP accumulation rate and AUC in leukemic cells did not change compared with administration of 3 g/m2 over 2 h. However, when the infusion rate was further reduced to 0.4 or 0.3 g/m2 over 2 h, resulting in steady-state plasma ara-C concentrations of less than 7 microM, 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.
27例难治性白血病患者接受了1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷）治疗，剂量为0.3至3.0g/m²，通过静脉输注，输注时间为1、2、4或24小时。在13例患者中，单次2小时输注3g/m²阿糖胞苷后，研究了外周血白血病细胞中阿糖胞苷在血浆中的药代动力学及其5'-三磷酸（阿糖胞苷三磷酸）的药代动力学。输注后1至2小时内，白血病细胞中阿糖胞苷三磷酸的积累保持线性。当阿糖胞苷三磷酸积累速率偏离线性时，血浆中阿糖胞苷的浓度比输注期间的稳态水平低5至20倍[8.1±4.4（标准差）μM]。在另外14例患者中进行了两次连续输注后，研究了血浆阿糖胞苷和细胞阿糖胞苷三磷酸的药代动力学。将阿糖胞苷剂量的输注时间在1、2和4小时之间变化（分别对应输注速率为3000、1500和750mg/m²/h），白血病细胞中阿糖胞苷三磷酸的积累速率没有实质性变化。随着输注时间的延长，白血病细胞中阿糖胞苷三磷酸的峰值浓度和浓度-时间曲线下面积（AUC）增加。尽管在2小时内输注1.0或0.5g/m²时，血浆中阿糖胞苷的稳态浓度和AUC成比例降低，但与2小时输注3g/m²相比，白血病细胞中阿糖胞苷三磷酸的积累速率和AUC没有变化。然而，当输注速率在2小时内进一步降低至0.4或0.3g/m²，导致血浆阿糖胞苷稳态浓度低于7μM时，阿糖胞苷三磷酸的积累速率和细胞内AUC均显著降低。在所有输注条件下，阿糖胞苷三磷酸的细胞消除速率保持恒定。这些发现支持以下结论：目前实施的大剂量阿糖胞苷治疗导致血浆阿糖胞苷浓度达到使循环白血病细胞中阿糖胞苷三磷酸积累饱和的水平。我们建议在未来的研究中评估200至250mg/m²/h的中等输注速率，作为目前使用的高得多的阿糖胞苷输注速率的替代方案。
