Coustère C, Mentré F, Sommadossi J P, Diasio R B, Steimer J L
INSERM U 194, Département de Biomathématiques, Bd de l'Hôpital, France.
Cancer Chemother Pharmacol. 1991;28(2):123-9. doi: 10.1007/BF00689701.
A compartmental model of the kinetics of 5-fluorouracil (5-FU) and its catabolites in humans is proposed. This model was developed using data from a previous study in which plasma levels and urinary amounts of unchanged drug and metabolites were quantitated after i.v. bolus injection of 500 mg/m2 5-FU in ten patients. Biliary excretion was also quantified in two subjects. The different processes, biochemical transformations, and urinary and biliary excretion were adequately described by first-order kinetics. The technique of multiresponse modelling was used for global fitting of all data for each patient. Satisfactory agreement was achieved between measured and predicted values. This model enabled accurate evaluation of pharmacokinetic parameters that could not be adequately calculated using a model-free analysis. The total clearance and elimination half-life of 5-FU and its catabolites are reported for all subjects. The estimated mean half-life was 6.9 +/- 3.9 min for unchanged 5-FU and 225 +/- 352, 7.6 +/- 4, and 9.6 +/- 7.7 min, respectively, for the three measured catabolites dihydrofluorouracil (FUH2), alpha-fluoro-beta-ureidopropionic acid (FUPA), and alpha-fluoro-beta-alanine (FBAL). The percentage of anabolic, catabolic, urinary, and biliary elimination in total clearance was also quantitated. Anabolic clearance accounted for 39% +/- 14% of total 5-FU clearance, with substantial variation occurring among patients. Urinary clearance represented 6.5% +/- 3.2%, 0.8% +/- 0.9%, 13.2% +/- 4.7%, and 98.2% +/- 2.5% of total clearance for 5-FU, FUH2, FUPA, and FBAL, respectively. The model was also satisfactorily fitted to the data of a patient deficient in dihydropyrimidine dehydrogenase, an enzyme previously thought to be the rate-limiting step for 5-FU catabolism. In this case, catabolism was highly reduced and urinary excretion of 5-FU increased up to 64% of total drug clearance. This first global model of the kinetics of 5-FU and all of its catabolites in patients given an i.v. bolus infusion of 500 mg/m2 5-FU represents a further step toward detailed comprehensive modeling of the kinetics of this drug.
本文提出了一种人体中5-氟尿嘧啶（5-FU）及其代谢产物动力学的房室模型。该模型是利用先前一项研究的数据开发的，在该研究中，对10名患者静脉推注500mg/m² 5-FU后，定量测定了未变化药物和代谢产物的血浆水平和尿量。还对两名受试者的胆汁排泄进行了定量。不同的过程、生化转化以及尿液和胆汁排泄均用一级动力学进行了充分描述。多响应建模技术用于对每位患者的所有数据进行整体拟合。测量值和预测值之间取得了令人满意的一致性。该模型能够准确评估使用无模型分析无法充分计算的药代动力学参数。报告了所有受试者5-FU及其代谢产物的总清除率和消除半衰期。未变化的5-FU估计平均半衰期为6.9±3.9分钟，三种测得的代谢产物二氢氟尿嘧啶（FUH2）、α-氟-β-脲基丙酸（FUPA）和α-氟-β-丙氨酸（FBAL）的半衰期分别为225±352、7.6±4和9.6±7.7分钟。还定量了合成代谢、分解代谢、尿液和胆汁消除在总清除率中的百分比。合成代谢清除率占5-FU总清除率的39%±14%，患者之间存在显著差异。尿液清除率分别占5-FU、FUH2、FUPA和FBAL总清除率的6.5%±3.2%、0.8%±0.9%、13.2%±4.7%和98.2%±2.5%。该模型也令人满意地拟合了二氢嘧啶脱氢酶缺乏患者的数据，该酶先前被认为是5-FU分解代谢的限速步骤。在这种情况下，分解代谢大大降低，5-FU的尿液排泄增加至总药物清除率的64%。这个第一个关于静脉推注500mg/m² 5-FU的患者中5-FU及其所有代谢产物动力学的整体模型代表了朝着该药物动力学详细综合建模迈出的又一步。
