Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, ATC code: L01BC02.

Fluorouracil fluorinated pyrimidine derivative, itself without antineoplastic effects. The inhibition of cell division occurs after metabolism by the active metabolites 5-fluorouridine triphosphate (FUTP) and 5-fluorodeoxyuridine monophosphate (FdUMP).

Known mechanisms of action:
• Blockage of DNA synthesis (inhibition of thymidilate synthetase by FdUMP).
• Inhibition of RNA synthesis (formation of a defective RNA by incorporation of FUTP).
• DNA strand breaks after incorporation of fluorodeoxyuridine triphosphate (phosphorylated FdUMP) into the DNA.
The inhibitory effects are particularly evident in cells that grow rapidly and thus absorb fluorouracil to a greater extent.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Half-life
After intravenous administration of fluorouracil (5-FU), the (monophasic) elimination half-life is 10– 20 minutes and is dose-dependent; a biphasic half-life of 8 and 40 minutes has been reported. Three hours after administration, 5-FU plasma levels are no longer measurable.

Distribution
The distribution corresponds to the total body fluid.
Fluorouracil crosses the blood-cerebrospinal fluid barrier.

Biotransformation
Approximately 85% of the administered dose is metabolized. Active metabolites are the intracellularly formed 5-fluorouridine triphosphate (FUTP) and 5-fluorodeoxyuridine monophosphate (FdUMP). In addition to the active metabolites, 5-FU is mainly metabolized in the liver to inactive metabolites (major metabolites: 5-fluorouridine, 5-fluorodeoxyuridine) and catabolized to uracil. Carbon dioxide, urea and other metabolites are also produced.

Elimination
15% of the administered amount is excreted unchanged within 6 hours by the kidneys, of which about 90% within the first hour.

Fluorouracil is further catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic 5,6-dihydro-fluorouracil (FUH2). The enzyme dihydropyrimidinase cleaves the pyrimidine ring to 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase splits FUPA to α-fluoro-β-alanine (FBAL), which is excreted in the urine. The activity of dihydropyrimidine dehydrogenase (DPD) is rate-limiting. DPD deficiency may increase the toxicity of fluorouracil (see sections 4.3 and 4.4).