Quantitation of 5-fluorouracil catabolism in human liver in vivo by three-dimensional localized 19F magnetic resonance spectroscopy.
The development of clinical applications of 19F magnetic resonance (MR) spectroscopy of 5-fluorouracil (5-FU) has been limited by the inability to localize 19F spectra to specific regions of interest, making it difficult to quantitate drug and metabolite concentrations accurately. To develop methodology for quantitation, we studied the liver of patients receiving rapid bolus i.v. injections of 5-FU. In serial studies, 5-FU disappeared from the liver within 17-26 min, and its catabolite, alpha-fluoro-beta-alanine (FBAL), rose to reach a plateau after 40 min. A high peak level of fluoro-ureido-propionic acid preceded that of FBAL in only one patient, and dihydrofluorouracil was never observed. During the plateau, we obtained MR imaging-directed 19F MR spectra localized using three-dimensional chemical shift imaging. The spin-lattice relaxation time of FBAL in liver, measured using a variable nutation angle method, was 1.6 +/- 0.2 s (mean +/- SD; n = 5). The concentration of FBAL at 60 +/- 10 min after injection was 1.0 +/- 0.2 mm in liver (mean +/- SD; n = 7). This amount represents approximately 20% of the injected dose and 1.4 times the initial hepatic 5-FU concentration. Our approach may permit one to obtain molar concentrations of fluoropyrimidine metabolites simultaneously in hepatic cancers and surrounding liver, and it helps expand pharmacokinetic modeling of fluoropyrimidine catabolism.
Li
C W
CW
Departments of Nuclear Magnetic Resonance, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Negendank
W G
WG
Padavic-Shaller
K A
KA
O'Dwyer
P J
PJ
Murphy-Boesch
J
J
Brown
T R
TR
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil