Metabolites of 5-fluorouracil in plasma and urine, as monitored by 19F nuclear magnetic resonance spectroscopy, for patients receiving chemotherapy with or without methotrexate pretreatment.
Metabolites of 5-fluorouracil in plasma and urine, as monitored by 19F nuclear magnetic resonance spectroscopy, for patients receiving chemotherapy with or without methotrexate pretreatment.
复制标题
通过 19F 核磁共振波谱监测接受或未接受甲氨蝶呤预处理的化疗患者血浆和尿液中 5-氟尿嘧啶的代谢情况。
作者：
William E. Hull;R. Port;Richard Herrmann;Bärbel Britsch;Werner Kunz
470 MHz (11.7 Tesla) 的 19F NMR 波谱已用于直接测量结肠癌患者静脉注射后血浆和尿液中 5-氟尿嘧啶 (FU) 及其含氟分解代谢物的水平。输注（10 分钟）60-230 mumol（8-30 mg）FU/kg，无论是否用甲氨蝶呤（5.1-12.5 mg/kg）预处理。对于 1.5 ml 样品，可定量的最低代谢物浓度在数据采集后 30 分钟内约为 15 +/- 5 microM，在 12 小时内约为 3 +/- 1 microM。 FU 的第一个和第二个分解代谢物，二氢氟尿嘧啶和 α-氟-β-脲基丙酸，在输注后约 10-90 分钟内表现出稳态行为，剂量依赖性血浆浓度为 5-40 µM（12 名患者，16 次治疗）。 5-15分钟后在血浆中检测到最终分解代谢物α-氟-β-丙氨酸（FBAL），其浓度增加的速率与FU剂量无关，而在FU消失时达到的最大浓度（1-2小时内FU小于5μM）是剂量依赖性的。血浆中 FU 的时间曲线下面积随剂量增加超过线性。几名患者的血浆中游离氟阴离子 (F-) 水平升高（63 个样本：中值 5 µM；最大值 33 µM）。在尿液中可以观察到所有上述分解代谢物和F-。在 pH 值大于或等于 7.3 的样本（甲氨蝶呤患者，由于碳酸氢盐输注）中，还发现了大量的 N-羧基-FBAL。 2 小时内 FU 和分解代谢物的尿排泄量为剂量的 2.6-30%（14 名患者，18 次治疗），24 小时内为 60-66%（3 名患者）。 2 小时尿液中 FU/肌酐的比率随 FU 剂量的增加而呈线性以上增加。尿氟浓度在 FU 输注后的第一天达到最高，并在 2-3 天后恢复到正常背景水平（四名患者）。在血浆或尿液中观察到的 FU 分解代谢物模式在治疗有反应者和无反应者之间或在 FU 单药治疗的患者和接受甲氨蝶呤预处理的患者之间没有显着差异。在血浆或尿液中未检测到细胞毒性 FU 合成代谢物（即核苷酸）（即小于 3 µM）。评估个体对 FU 的反应需要在肿瘤组织中进行检测。血浆或尿液中未检测到源自 FBAL 的可能有毒代谢产物，例如 2-氟乙酸盐或 2-氟柠檬酸盐（即小于 3 微摩尔）。（摘要截断为 400 字）
19F NMR spectroscopy at 470 MHz (11.7 Tesla) has been used to directly measure the levels of 5-fluorouracil (FU) and its fluorine-containing catabolites in plasma and urine of colon cancer patients after i.v. infusion (10 min) of 60-230 mumol (8-30 mg) FU/kg, either with or without pretreatment with methotrexate (5.1-12.5 mg/kg). With a 1.5-ml sample the minimum metabolite concentration that can be quantified is approximately 15 +/- 5 microM within 30 min and 3 +/- 1 microM within 12 h of data acquisition. The first and second catabolites of FU, dihydrofluorouracil and alpha-fluoro-beta-ureidopropanoic acid, exhibit steady-state behavior with dose-dependent plasma concentrations of 5-40 microM for approximately 10-90 min after infusion (12 patients, 16 treatments). The final catabolite alpha-fluoro-beta-alanine (FBAL) was detected in plasma after 5-15 min, and the rate at which its concentration increased was independent of FU dose, while the maximum concentration reached at about the time FU disappeared (FU less than 5 microM in 1-2 h) was dose-dependent. The area under the time curve for FU in plasma increased more than linearly with dose. Several patients showed elevated levels of free fluoride anion (F-) in plasma (63 samples: median, 5 microM; maximum, 33 microM). In urine all of the above catabolites and F- could be observed. In samples with pH greater than or equal to 7.3 (methotrexate patients, due to bicarbonate infusion) N-carboxy-FBAL was also found in significant amounts. Urinary excretion of FU and catabolites amounted to 2.6-30% of the dose within 2 h (14 patients, 18 treatments) and 60-66% within 24 h (three patients). The ratio FU/creatinine in 2-h urine increased more than linearly with FU dose. Urinary fluoride concentration reached a maximum during the first day after FU infusion and returned to normal background levels after 2-3 days (four patients). The pattern of FU catabolites observed in plasma or urine did not differ significantly between responders and nonresponders to therapy or between patients with FU monotherapy and patients with methotrexate pretreatment. Cytotoxic FU anabolites, i.e., nucleotides, were not detected in plasma or urine (i.e., are less than 3 microM). Their detection in tumor tissue will be required for an assessment of individual responsiveness to FU. Possible toxic metabolic products derivable from FBAL, e.g., 2-fluoroacetate or 2-fluorocitrate, were not detected (i.e., are less than 3 microM) in plasma or urine.(ABSTRACT TRUNCATED AT 400 WORDS)