Ho D H, Covington W P, Pazdur R, Brown N S, Kuritani J, Newman R A, Raber M N, Krakoff I H
Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Drug Metab Dispos. 1992 Nov-Dec;20(6):936-40.
Phase I clinical trials of the combination of oral uracil with ftorafur (Ft) were conducted in patients with solid tumors over either a 5-day (345 mg/m2/day) or a 28-day (160 mg/m2/day) period. The uracil dose, which was four times the Ft dose (molar basis), was previously shown to be optimal at inhibiting the degradation of 5-fluorouracil (5-FU). Pharmacology was performed on the first dose of the first day of therapy. Ft was measured by HPLC, whereas uracil and 5-FU were measured using GC/MS. Plasma levels were highest for Ft, followed by uracil and 5-FU at all time points. Peak and trough levels after selected subsequent doses were also measured; these varied in the individual from day to day. Maximum plasma levels (Cpmax) for Ft, uracil, and 5-FU except in one patient were achieved at 0.6-2.1 hr, 0.6-4.1 hr, and 0.7-2.0 hr, respectively. Generally, lower doses yielded more rapid decay of 5-FU and uracil levels than did higher doses. No correlation was observed between myelotoxicities (granulocytopenia and leukopenia) and the Cpmax and AUC0-6hr of Ft (p > 0.2). However, after the highest uracil and Ft dose (approximately 300 mg/m2/Ft study dose), the Cpmax and AUC0-6hr values of 5-FU revealed significant differences (p < 0.05) in three patients each with and without myelotoxicity. These associations were similarly observed with uracil. Our findings thus indicate that measuring plasma uracil and more importantly, the 5-FU levels, may predict hematological toxicity and enable subsequent dose adjustments.
对实体瘤患者进行了口服尿嘧啶与替加氟（Ft）联合用药的I期临床试验，给药期为5天（345mg/m²/天）或28天（160mg/m²/天）。尿嘧啶剂量是Ft剂量的四倍（摩尔比），先前已证明该剂量在抑制5-氟尿嘧啶（5-FU）降解方面是最佳的。在治疗第一天的第一剂给药后进行了药理学研究。Ft通过高效液相色谱法测定，而尿嘧啶和5-FU使用气相色谱/质谱联用仪测定。在所有时间点，Ft的血浆水平最高，其次是尿嘧啶和5-FU。还测量了选定后续剂量后的峰浓度和谷浓度；这些浓度在个体之间每天都有所不同。除一名患者外，Ft、尿嘧啶和5-FU的最大血浆浓度（Cpmax）分别在0.6 - 2.1小时、0.6 - 4.1小时和0.7 - 2.0小时达到。一般来说，较低剂量比较高剂量导致5-FU和尿嘧啶水平的衰减更快。未观察到骨髓毒性（粒细胞减少和白细胞减少）与Ft的Cpmax和AUC0 - 6hr之间存在相关性（p>0.2）。然而，在使用最高尿嘧啶和Ft剂量（约300mg/m²/Ft研究剂量）后，5-FU的Cpmax和AUC0 - 6hr值在有和没有骨髓毒性的三名患者中均显示出显著差异（p<0.05）。尿嘧啶也观察到了类似的关联。因此，我们的研究结果表明，测量血浆尿嘧啶，更重要的是测量5-FU水平，可能预测血液学毒性并实现后续剂量调整。
