Petit E, Milano G, Lévi F, Thyss A, Bailleul F, Schneider M
Centre Antoine Lacassagne, Nice, France.
Cancer Res. 1988 Mar 15;48(6):1676-9.
A circadian rhythm in the plasma concentration of 5-fluorouracil (5-FUra) is demonstrated in seven patients receiving this drug as a continuous venous infusion at a constant rate for 5 days. All patients had stage C bladder carcinoma and received cis-diamminedichloroplatinum(II) (45-91 mg/m2) on day 1 as a 30-min venous infusion at 5 p.m. Continuous venous infusion of 5-FUra (450-966 mg/m2/day) was started on day 2 at 8:30 a.m. via a volumetric pump and lasted for 5 days (until day 6). Blood samples were obtained on EDTA every 3 h on days 2, 4, and 6 on each patient (20 samples/patient). 5-FUra plasma concentration was determined by high performance liquid chromatography. Data were analyzed by both multiple analysis of variance and cosinor. Mean lowest and highest values (+/- SEM) were, respectively, 254 +/- 33 ng/ml at 1 p.m. and 584 +/- 160 ng/ml at 1 a.m. (F = 2.3; P less than 0.03). Because of large intersubject differences in 24-h mean plasma concentration, data were also expressed as percentages of each patient's 24-h mean. Both analysis of variance and cosinor analysis further validated (P less than 0.0001) a circadian rhythm with a double amplitude (total extent of variation) of 50% of the 24-h mean and an acrophase located at approximately 1 a.m. (estimated time of peak). Such findings warrant a thorough scrutiny at the chronopharmacology of anticancer drugs when designing continuous infusion schedule. A circadian modulation of the infusion rate of this drug may further optimize the therapeutic index of such treatment modality.
在7例以恒定速率持续静脉输注5-氟尿嘧啶（5-FUra）5天的患者中，证实了其血浆浓度存在昼夜节律。所有患者均为C期膀胱癌，于第1天下午5点接受30分钟静脉输注顺二氯二氨铂（II）（45 - 91 mg/m²）。第2天上午8:30通过容量泵开始持续静脉输注5-FUra（450 - 966 mg/m²/天），持续5天（至第6天）。在第2、4和6天，每3小时对每位患者采集一次EDTA抗凝血样本（每位患者20个样本）。通过高效液相色谱法测定5-FUra血浆浓度。采用多因素方差分析和余弦分析对数据进行分析。平均最低值和最高值（±SEM）分别为下午1点时的254±33 ng/ml和凌晨1点时的584±160 ng/ml（F = 2.3；P＜0.03）。由于24小时平均血浆浓度存在较大的个体间差异，数据也以每位患者24小时平均值的百分比表示。方差分析和余弦分析均进一步验证（P＜0.0001）了昼夜节律，其双振幅（总变化程度）为24小时平均值的50%，峰相位位于凌晨1点左右（估计峰值时间）。这些发现表明，在设计持续输注方案时，有必要对抗癌药物的时辰药理学进行深入研究。对该药物输注速率进行昼夜调节可能会进一步优化这种治疗方式的治疗指数。
