CLINICAL PHARMACOLOGY
There is evidence that the metabolism of fluorouracil
in the anabolic pathway blocks the methylation reaction
of deoxyuridylic acid to thymidylic acid. In this manner
fluorouracil interferes with the synthesis of deoxyribonucleic
acid (DNA) and to a lesser extent inhibits the formation
of ribonucleic acid (RNA). Since DNA and RNA are essential
for cell division and growth, the effect of fluorouracil
may be to create a thymine deficiency which provokes unbalanced
growth and death of the cell. The effects of DNA and RNA
deprivation are most marked in those cells which grow
more rapidly and which take up fluorouracil at a more
rapid rate.
Following intravenous injection, fluorouracil distributes
into tumors, intestinal mucosa, bone marrow, liver and
other tissues throughout the body. In spite of its limited
lipid solubility, fluorouracil diffuses readily across
the blood-brain barrier and distributes into cerebrospinal
fluid and brain tissue.
Seven to twenty percent of the parent drug is excreted
unchanged in the urine in six hours; of this over 90%
is excreted in the first hour. The remaining percentage
of the administered dose is metabolized, primarily in
the liver. The catabolic metabolism of fluorouracil results
in degradation products (e.g., CO2 urea and a-fluoro-b-alanine)
which are inactive. The inactive metabolites are excreted
in the urine over the next 3 to 4 hours. When fluorouracil
is labeled in the six carbon position, thus preventing
the 14C metabolism to CO2, approximately 90% of the total
radioactivity is excreted in the urine. When fluorouracil
is labeled in the two carbon position approximately 90%
of the total radioactivity is excreted in expired CO2.
Ninety percent of the dose is accounted for during the
first 24 hours following intravenous administration.
Following intravenous administration of fluorouracil, the
mean half-life of elimination from plasma is approximately
16 minutes, with a range of 8 to 20 minutes, and is dose
dependent. No intact drug can be detected in the plasma
three hours after an intravenous injection.
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