Harris B E, Song R, Soong S J, Diasio R B
Department of Pharmacology, University of Alabama, Birmingham 35294.
Cancer Res. 1990 Jan 1;50(1):197-201.
The activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells and plasma concentration of 5-fluorouracil (FUra) were simultaneously determined in cancer patients receiving FUra by protracted continuous infusion (300 mg/m2/day). Blood samples were drawn every 3 h over 24-h period and the resulting DPD and FUra values analyzed for circadian periodicity. In the seven patients studied, a circadian rhythm of DPD activity was observed (P less than 0.00001, Cosinor analysis) with the peak of activity at 1 a.m. (0.197 +/- 0.007 nmol/min/mg) and the trough at a 1 p.m. (0.113 +/- 0.007 nmol/min/mg). In addition, a circadian rhythm was observed for the plasma concentrations of FUra obtained over a 24-h period (P less than 0.00001, Cosinor analysis) with peak values (27.4 +/- 1.3 ng/ml) occurring at 11 a.m. and trough values (5.6 +/- 1.3 ng/ml) occurring at 11 p.m. The ratio of the maximum concentration of FUra to the minimum concentration observed was almost 5-fold. This study demonstrates a circadian variation of DPD activity in human peripheral blood mononuclear cells and a circadian variation of FUra plasma levels in patients receiving FUra by protracted continuous infusion. An inverse relationship between the circadian patterns of DPD activity and FUra plasma levels was also noted, suggesting that an association may exist between DPD activity and FUra plasma concentration. Further evidence of an association between DPD activity in peripheral blood mononuclear cells and plasma FUra concentration was demonstrated by a linear relationship between the two parameters in all patients (r = -0.627) and within individual patients (-0.978 less than r less than -0.742). With the recent advent of programmable pumps, information on the circadian pattern of FUra and/or DPD may be useful in planning continuous infusion schedules in order that optimal plasma drug concentration may be maintained over a 24-h cycle, thereby enhancing the therapeutic efficacy of FUra administered by continuous infusion.
通过持续静脉输注（300mg/m²/天）接受5-氟尿嘧啶（FUra）治疗的癌症患者，同时测定其外周血单核细胞中二氢嘧啶脱氢酶（DPD）的活性以及血浆中FUra的浓度。在24小时内每3小时采集一次血样，并对所得的DPD和FUra值进行昼夜节律分析。在研究的7名患者中，观察到DPD活性存在昼夜节律（P＜0.00001，余弦分析），活性峰值出现在凌晨1点（0.197±0.007nmol/min/mg），谷值出现在下午1点（0.113±0.007nmol/min/mg）。此外，在24小时内获得的血浆FUra浓度也观察到昼夜节律（P＜0.00001，余弦分析），峰值（27.4±1.3ng/ml）出现在上午11点，谷值（5.6±1.3ng/ml）出现在晚上11点。观察到的FUra最大浓度与最小浓度之比接近5倍。本研究表明，在接受持续静脉输注FUra的患者中，人外周血单核细胞中DPD活性存在昼夜变化，血浆中FUra水平也存在昼夜变化。还注意到DPD活性的昼夜模式与FUra血浆水平之间呈负相关，这表明DPD活性与FUra血浆浓度之间可能存在关联。所有患者中这两个参数之间的线性关系（r = -0.627）以及个体患者中（-0.978＜r＜-0.742）进一步证明了外周血单核细胞中DPD活性与血浆FUra浓度之间存在关联。随着可编程泵的出现，关于FUra和/或DPD昼夜模式的信息可能有助于规划持续输注方案，以便在24小时周期内维持最佳血浆药物浓度，从而提高持续输注FUra的治疗效果。
