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Metabolites of 5-Fluorouracil in Plasma and Urine, as Monitored by ¹⁹F Nuclear Magnetic Resonance Spectroscopy, for Patients Receiving Chemotherapy with or without Methotrexate Pretreatment¹

German Cancer Research Center, Central Spectroscopy [W. E. H.], Institute of Biochemistry [R. E. P., W. K.], Neuenheimer Feld 280, D-6900 Heidelberg; and University of Heidelberg, Department of Medicine [R. H., B. B.], D-6900 Heidelberg; FRG

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 µmol (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 than can be quantified is approximately 15 ± 5 µM within 30 min and 3 ± 1 µM within 12 h of data acquisition. The first and second catabolites of FU, dihydrofluorouracil and -fluoro-ß-ureidopropanoic acid, exhibit steady-state behavior with dose-dependent plasma concentrations of 5–40 µM for approximately 10–90 min after infusion (12 patients, 16 treatments). The final catabolite -fluoro-ß-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 < 5 µM 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 µM; maximum, 33 µM).

In urine all of the above catabolites and F^- could be observed. In samples with pH 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 < 3 µM). 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 < 3 µM) in plasma or urine. This leads us to propose that the release of fluoride from FBAL results in the deactivation of the transaminase required for the catabolism of FBAL.

¹ This paper is dedicated to Professor Dr. Erich Hecker on the occasion of his 60th birthday and was supported in part by a grant from the Tumor Center, Heidelberg/Mannheim (Colon Carcinoma Project).

² To whom requests for reprints should be addressed.

³ Present address: Klinikum Charlottenburg der Freien Universität, D-1000 Berlin 19, FRG.

Received 5/13/87. Revised 11/30/87. Accepted 12/10/87.

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