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

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)