A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea
A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea
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DOI：
10.1182/blood.v91.5.1533.1533_1533_1541
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发表时间：
1998-03-01
期刊：
影响因子：
20.3
通讯作者：
Rowinsky, EK
中科院分区：
文献类型：
--
作者：
Rodriguez, GI;Kuhn, JG;Rowinsky, EK
尽管羟基脲广泛用于治疗恶性和非恶性疾病，并且最近对其潜在治疗应用的认识有所扩大，但很少有关于羟基脲的药代动力学（PK）行为和口服生物利用度的详细研究。由于担心口服给药后，羟基脲的PK行为和生物利用度可能存在显著的个体间变异性，因此对胃肠外给药方案进行了评价。在这项PK和生物利用度研究中，29例晚期实体恶性肿瘤患者随机接受2，000 mg羟基脲治疗，口服或30分钟静脉（IV）输注给药，同时采集大量血浆和尿液样本用于PK研究。在接受3周的羟基脲治疗（80 mg/kg口服，每3天1次，随后为1周洗脱期）后，患者交叉至替代给药途径，此时重复进行广泛的PK研究。3天后，患者继续接受80 mg/kg羟基脲口服治疗，每3天一次，持续3周，随后休息1周。此后，每3天经口给予80 mg/kg羟基脲。29例患者中有22例在口服和IV羟基脲治疗后进行了广泛的血浆和尿液采样。口服生物利用度（F）平均为108%。此外，F的个体间变异性较低，如22个个体中的19个F值在85%至127%的狭窄范围内和17%的适度变异系数所示。口服给药后达到最大血药浓度（C-max）的时间平均为1.22小时，平均滞后时间为0.22小时。除了C-max（IV给药后升高19.5%）外，口服和IV羟基脲的PK特征非常相似。血浆中羟基脲的分布符合线性二室模型。口服和IV羟基脲的初始调和平均半衰期分别为1.78和0.63小时，调和平均终末半衰期分别为3.32和3.39小时。对于IV羟基脲，口服给药后，全身清除率平均为76.16 mL/min/m2，稳态时的平均分布容积为19.71 L/m2，而Cl-口服/F和V-口服/F的平均值分别为73.16 mL/min/m2和19.65 L/m2。经口和IV给药后，以原型排泄至尿液中的羟基脲给药剂量百分比几乎相同-分别为36.84%和35.82%。此外，两种途径给药后，羟基脲的急性毒性作用相似。研究了相关PK参数与主要毒性（中性粒细胞减少症）之间的关系，但未发现明显的药效学关系。从PK、生物利用度和毒理学角度来看，这些结果表明，除了无法经口给药和/或重度胃肠道损害的情况外，通过IV途径给药羟基脲没有明显的优势。(C)1998年，美国血液学会。
Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2,000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (C-max) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for C-max, which was 19.5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m(2) and the mean volume of distribution at steady-state was 19.71 L/m(2), whereas Cl-oral/F and V-oral/F averaged 73.16 mL/min/m(2) and 19.65 L/m(2), respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration-36.84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment. (C) 1998 by The American Society of Hematology.