Vassal G, Challine D, Koscielny S, Hartmann O, Deroussent A, Boland I, Valteau-Couanet D, Lemerle J, Lévi F, Gouyette A
Clinical Pharmacology Laboratory (CNRS URA147, INSERM U140), Institut Gustave-Roussy, Villejuif, France.
Cancer Res. 1993 Apr 1;53(7):1534-7.
In bone marrow transplantation, high-dose busulfan is given p.o., usually every 6 h over 4 consecutive days. Since this repeated administration might alter busulfan disposition, fluctuations in busulfan plasma levels were studied over the 4-day treatment period in 21 children (median age, 5 years) with malignant solid tumors. In addition, urinary excretion of unchanged busulfan was measured every 6 h in 4 patients. Busulfan (37.5 mg/m2 for 16 doses) was given on an empty stomach at 12 p.m., 6 p.m., midnight, and 6 a.m. for 4 consecutive days, starting at 12 p.m. Trough plasma levels, i.e., concentration 6 h after each dose and just before the next one, and urinary excretion of busulfan were measured using a gas chromatography-mass spectrometry assay. Busulfan trough plasma levels exhibited a significant circadian rhythm with a higher mean level at 6 a.m. compared to that at 12 p.m., 6 p.m., and midnight. This rhythm was characterized by a double amplitude (mean +/- SD) of 42 +/- 14% and an acrophase (maximum) occurring at 5:48 a.m. +/- 115 min. In addition, once the steady state was reached, no decreasing trend was observed in any patient. Busulfan renal clearance proved to be low since only 5.4 +/- 1.2% of the given dose were excreted unchanged in urine. In the 4 patients studied, busulfan urinary excretion exhibited a significant circadian rhythm which was apparently linked to the physiological circadian rhythm in urinary output. Ten of 20 evaluable patients developed hepatic venoocclusive disease (HVOD). A significant circadian rhythm in the plasma level was found in both HVOD and non-HVOD patients with no difference between the two groups with regard to the 24-h mean, amplitude, or acrophase. Thus, the circadian changes in busulfan trough plasma levels observed at the steady state were not related to the occurrence of HVOD in these children with solid tumors. Moreover, since this rhythm was stable from day 2 to day 4, it should not compromise dose adjustment.
在骨髓移植中，高剂量白消安通过口服给药，通常连续4天每6小时给药一次。由于这种重复给药可能会改变白消安的处置情况，因此研究了21名（中位年龄5岁）患有恶性实体瘤的儿童在4天治疗期内白消安血浆水平的波动情况。此外，对4名患者每6小时测量一次未改变的白消安的尿排泄量。白消安（16剂，37.5mg/m²）于中午12点、下午6点、午夜和凌晨6点空腹给药，连续4天，从中午12点开始。使用气相色谱-质谱分析法测量谷值血浆水平，即每次给药后6小时及下次给药前的浓度，以及白消安的尿排泄量。白消安谷值血浆水平呈现出显著的昼夜节律，凌晨6点的平均水平高于中午12点、下午6点和午夜。这种节律的特征是双振幅（平均值±标准差）为42±14%，高峰相位（最大值）出现在凌晨5:48±115分钟。此外，一旦达到稳态，未观察到任何患者有下降趋势。白消安的肾清除率较低，因为仅5.4±1.2%的给药剂量以未改变的形式经尿液排泄。在研究的4名患者中，白消安的尿排泄呈现出显著的昼夜节律，这显然与尿量的生理昼夜节律有关。20名可评估患者中有10名发生了肝静脉闭塞病（HVOD）。在HVOD患者和非HVOD患者中均发现血浆水平存在显著的昼夜节律，两组在24小时平均值、振幅或高峰相位方面无差异。因此，在这些实体瘤儿童中，稳态时观察到的白消安谷值血浆水平的昼夜变化与HVOD的发生无关。此外，由于这种节律从第2天到第4天是稳定的，因此不应影响剂量调整。
