Gusella M, Crepaldi G, Barile C, Bononi A, Menon D, Toso S, Scapoli D, Stievano L, Ferrazzi E, Grigoletto F, Ferrari M, Padrini R
Oncology Division, Rovigo General Hospital, Rovigo, Italy.
Ann Oncol. 2006 Nov;17(11):1656-60. doi: 10.1093/annonc/mdl284. Epub 2006 Sep 12.
The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied.
One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle.
The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients.
A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.
静脉推注5-氟尿嘧啶（5-FU）后的药代动力学与毒性之间的关系尚未得到广泛研究。
181例接受5-FU联合亚叶酸钙辅助治疗结肠癌的患者作为研究对象。在第1、3和5周期的第2天测定5-FU药代动力学；在下一周期记录不良反应的类型和分级。
第1周期测得的5-FU曲线下面积（AUC）在146至1236 mg·min/l之间，与药物剂量、患者体重（BW）和性别显著相关，女性的AUC较高。这些协变量仅解释了AUC变异性的23%。AUC和年龄是区分毒性（≥2级）和非毒性周期（<2级）的唯一协变量，最佳AUC截止值为596 mg·min/l。由于80例患者出现毒性反应，在剂量减少后的后续周期中这种相关性消失。
提出了一种计算初始5-FU剂量的方法，该方法考虑了患者体重、性别和目标AUC为596 mg·min/l。然而，似乎5-FU毒性的很大一部分与药代动力学因素无关，剂量调整仍必须基于仔细的临床监测。
