Tumor, normal tissue, and plasma pharmacokinetic studies of fluorouracil biomodulation with N-phosphonacetyl-L-aspartate, folinic acid, and interferon alfa.
OBJECTIVE
To evaluate the effect of N-phosphonacetyl-L-aspartate (PALA), folinic acid (FA), and interferon alfa (IFN-alpha) biomodulation on plasma fluorouracil (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention after [18F]-fluorouracil (5-[18F]-FU) administration.


METHODS
Twenty-one paired pharmacokinetic studies were completed on patients with colorectal, gastric, and hepatocellular cancer, utilizing positron emission tomography (PET), which allowed the acquisition of tumor, normal tissue, and plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first PET study was completed when the patient was biomodulator-naive and was repeated on day 8 after the patient had been treated with either PALA, FA, or IFN-alpha in recognized schedules.


RESULTS
TBF was an important determinant of tumor radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled metabolites and catabolites. After treatment with PALA, TBF decreased (four of four patients; P = .043), as did tumor radioactivity exposure (five of five patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment, there were no differences observed in whole-body metabolism, plasma 5FU clearance, or tumor and liver pharmacokinetics. IFN-alpha had measurable effects on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow.


CONCLUSIONS
The administration of PALA and IFN-alpha produced measurable changes in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No changes were observed after FA administration. In vivo effects may negate the anticipated therapeutic advantage of 5FU biomodulation with some agents.
Harte
R J
RJ
Medical Research Council, Cancer Research Campaign Positron Emission Tomography Research Group, Imperial College School of Medicine, London, United Kingdom.
Matthews
J C
JC
O'Reilly
S M
SM
Tilsley
D W
DW
Osman
S
S
Brown
G
G
Luthra
S J
SJ
Brady
F
F
Jones
T
T
Price
P M
PM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D002955:Leucovorin / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D012039:Regional Blood Flow; D013274:Stomach Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D014055:Tomography, Emission-Computed
D000964:Antimetabolites, Antineoplastic; D016898:Interferon-alpha; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D002955:Leucovorin; D005472:Fluorouracil