Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients
Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients
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DOI：
10.1038/sj.bmt.1701355
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发表时间：
1998-09-01
影响因子：
4.8
通讯作者：
Nicholls, PJ
中科院分区：
文献类型：
--
作者：
Al-Rawithi, S;El-Yazigi, A;Nicholls, PJ
随机选择16例骨髓移植受者，观察丙烯醛（ACRO）及其母体药物环磷酰胺（CP）预处理后的尿排泄和药代动力学。患有再生障碍性贫血的患者（n = 3）以每天50 mg/kg的剂量静脉内（i. v.）在Ih。白血病患者（n = 13）给予白消安联合CP，剂量为50 mg/kg，静脉输注1小时，持续4天，或CP剂量为60 mg/kg，静脉输注1小时，每天持续2天，然后全身照射。首次CP给药开始后，采集系列血浆样本和尿液。通过毛细管气相色谱法分析CP，而通过液相色谱法测量尿液中的ACRO。CP的血浆浓度-时间数据符合二室模型，平均值和s.e.m.观察到的α、β、V-ss、总清除率和肾清除率值分别为1.29（0.31）h（-1）、0.17（0.03）h（-1）、0.67（0.13）l/kg、0.14（0.02）l/h.kg和0.0188（0.0052）l/h.kg。平均值和s.e. m在此期间以ACRO形式排泄的CP分数（f（mu））和24小时尿ACRO/肌酐浓度比（C-mu（n））分别为1.96（0.35%）和9.11（2.19）μ g ACRO/mg肌酐。2例患者发生出血性膀胱炎（HC）。这两名患者在第一和第二个4小时尿液收集期排出的ACRO均显著增加（P < 0.01）。然而，这两名患者的ACRO的f（mu）或C-mu（n）与其他患者之间无显著差异。这表明，尿液中ACRO的出现率比累积排泄量对HC的发展更为重要。
The urinary excretion and pharmacokinetics of acrolein (ACRO) and its parent drug cyclophosphamide (CP) were investigated in 16 randomly selected bone marrow transplant (BMT) recipients when CP was used for conditioning. Patients suffering from aplastic anemia (n = 3) received a 4-day course of CP at a dose of 50 mg/kg daily infused intravenously (i.v.) over Ih. Patients with leukemia (n = 13) were given either a combination of busulphan followed by CP at a dose of 50 mg/kg infused i.v, over Ih for 4 days, or CP at a dose of 60 mg/kg by i.v. infusion over 1 h daily for 2 days followed by total body irradiation. Serial plasma samples and urine were collected after the start of the first CP dose. CP was analyzed by capillary gas chromatography, whereas ACRO was measured in urine by liquid chromatography. The plasma concentration-time data for CP conformed to the two-compartment model and the mean and s.e.m. values of alpha, beta, V-ss, total clearance, and renal clearance observed were 1.29 (0.31) h(-1), 0.17 (0.03) h(-1), 0.67 (0.13) l/kg, 0.14 (0.02) I/h.kg, and 0.0188 (0.0052) l/h.kg, respectively. The mean and s.e.m. values of fraction of CP excreted in the form of ACRO during this interval (f(mu)) and ratio of the 24-h urinary concentration of ACRO/creatinine (C-mu(n)) were 1.96 (0.35%) and 9.11 (2.19) mu g of ACRO/mg of creatinine, respectively. Two patients developed hemorrhagic cystitis (HC). Each of these two patients excreted significantly (P < 0.01) more ACRO in the first and second 4-h urine collection periods. However, there was no significant difference in f(mu) or C-mu(n) of ACRO between either of these two patients and the rest. This suggests that the rate of appearance of ACRO in urine is more crucial for developing HC than the cumulative amount excreted.