ALTERATION OF THE PHARMACOKINETICS OF HIGH-DOSE ARA-C BY ITS METABOLITE, HIGH ARA-U IN PATIENTS WITH ACUTE-LEUKEMIA
ALTERATION OF THE PHARMACOKINETICS OF HIGH-DOSE ARA-C BY ITS METABOLITE, HIGH ARA-U IN PATIENTS WITH ACUTE-LEUKEMIA
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DOI：
10.1200/jco.1983.1.12.763
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发表时间：
1983-01-01
影响因子：
45.3
通讯作者：
CHENG, YC
中科院分区：
文献类型：
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作者：
CAPIZZI, RL;YANG, JL;CHENG, YC
高剂量阿糖胞苷 (HiDAC) 静脉注射 3 小时的药代动力学对 5 名急性白血病复发和/或缓解期间的患者进行了 3 g/m2 输注研究。 13 次输注期间 ara-C [阿糖胞苷] 的表观稳态血浆水平平均为 115 .+-。 32 微米停止输注后，ara-C 迅速从血浆中清除。 ara-C 的表观输注后动力学呈三指数，分布半衰期为 16 分钟，消除半衰期为 1.8 小时和 6 小时。总清除量平均为 86 l/h，平均停留时间为 0.47 小时。疾病状态（复发或缓解）对ara-C的药代动力学特征没有明显影响。 ara-U[尿苷阿拉伯糖苷]的峰值水平平均为310μM并且代谢物具有3.75小时的平均表观消除半衰期。尽管在随后输注ara-C时ara-U持续保持在约100μM，但随着HiDAC的重复输注，血浆中没有进一步积累ara-U。体外研究表明ara-U可以对脱氧胞苷(dCyd)脱氨酶活性产生抑制作用。对于胞苷(Cyd)-dCyd脱氨酶，ara-U的Ki与ara-C的Km之比为40:1。在ara-C消除的γ相期间，血浆中ara-U:ara-C的比例至少为100:1。 ara-U 可能延迟 ara-C 的全身分解代谢。 HiDAC 输注终止后两到三小时，ara-C CSF：血浆比率为 1-3：1，这是具有潜在治疗意义的特征。脑脊液中 ara-C 的消除速度较慢也可能有助于血浆 γ 半衰期。
The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a 3-h i.v. infusion at 3 g/m2 were studied in 5 patients with acute leukemia during relapse and/or remission of their disease. Apparent steady state plasma levels of ara-C [cytosine arabinoside] during 13 infusions averaged 115 .+-. 32 .mu.M. Upon cessation of the infusion, ara-C was rapidly cleared from the plasma. The apparent postinfusion kinetics of ara-C were triexponential with a distribution half-life of 16 min and elimination half-lives of 1.8 h and 6 h. Total clearance averaged 86 l/h and mean residence time averaged 0.47 h. Disease status (relapse or remission) had no apparent effect on the pharmacokinetic characteristics of ara-C. Peak levels of ara-U [uridine arabinoside] averaged 310 .mu.M and the metabolite had an average apparent elimination half-life of 3.75 h. Despite the persistence of ara-U at about 100 .mu.M at the time of administration of subsequent infusions of ara-C, there was no further accumulation of ara-U in the plasma with repetitive infusions of HiDAC. In vitro studies indicate that ara-U can exert an inhibitory effect on deoxycytidine (dCyd) deaminase activity. The ratio of the Ki of ara-U to the Km of ara-C for cytidine (Cyd)-dCyd deaminase is 40:1. During the gamma phase of ara-C elimination, the ratio of ara-U:ara-C in plasma is at least 100:1. A retardation of systemic catabolism of ara-C by ara-U is possible. Two to three hours after the termination of the HiDAC infusion, the ara-C CSF: plasma ratio is 1-3:1, a feature of potential therapeutic significance. The slower elimination of ara-C from the CSF may also contribute to the plasma gamma half-life.