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Pharmacotherapeutic Group: Antineoplastic agents, antimetabolites, pyrimidine analogues. ATC Code: L01BC02.
Pharmacology: Pharmacodynamics: The antimetabolite fluorouracil constitutes a fluorinated pyrimidine. Fluorouracil is enzymatically activated to deoxy-fluorouracil monophosphate. It inhibits the activity of thymidylate synthase and thus deoxythymidine monophosphate synthesis through complex formation. This results in phase-specific DNA-synthesis inhibition. Furthermore, deoxy-fluoronucleosides inhibit de novo synthesis of pyrimidine nucleotides.
Calcium folinate with fluorouracil and thymidylate synthase form a relatively stable ternary complex and thus prolong the inhibiting action of fluorouracil on thymidylate synthase. The result is the increased cytotoxic effect of fluorouracil.
Fluorouracil has a phase-specific action in the cell cycle, particularly on the S-phase. The effect of the substance in rapidly proliferating tissue (bone marrow, skin and mucosa) is particularly pronounced.
Pharmacokinetics: Fluorouracil is only partially absorbed orally (0 - 80%).
The substance exhibits a distribution of 0.12 l/kg BW (following 15 mg/kg BW IV) and can be found especially in rapidly proliferating tissue like bone marrow, intestinal mucosa and neoplasia; fluorouracil passes the blood-brain barrier.
Metabolisation takes place in the liver and is similar to uracil metabolisation. Fluorouracil is rapidly transformed enzymatically into the active metabolite dihydro-fluorouracil, which exhibits a substantially longer half-life period than fluorouracil. Other non-toxic metabolites are carbon dioxide and urea.
The plasma half-life (alpha phase) is between 8 and 22 minutes. The elimination half-life (beta phase) reaches approx. 20 hours due to the active metabolites in the tissue and is dose-dependent.
Fluorouracil (60 - 80%) is primarily exhaled by the lungs as carbon dioxide. Fluorouracil is secondarily excreted unchanged by the renal system (approx. 7 - 20%), approx. 90% of which is excreted within the first hour. Renal clearance is approximately 170-180 ml/min. In impaired renal function, the substance is excreted slowly.
Maximum concentration in the liquor is reached after approximately 1.5 - 2 hours and accounts for approx. 50% of plasma concentration.
Kinetics in special clinical situations: Despite the low proportion (approx. 15%) eliminated renally, an adequate dose adjustment depending on the degree of renal insufficiency and the reaction of the individual patient is indicated due to impaired bone marrow function in azotaemia (due to renal insufficiency) and potential interference with the thrombocytes. In impaired liver function a dose adjustment should also be taken into consideration.
Toxicology: Preclinical safety data: Toxicity: The cell division inhibiting effect of fluorouracil mainly affects rapidly proliferating tissues - both tumorigenic and healthy tissues.
Accordingly, the toxicities show particularly in bone marrow, with leucopenia, thrombocytopenia, gastrointestinal bleeding and secondarily in infections.
Reproduction toxicity / mutagenicity / carcinogenicity: In different in vitro cultures, Fluorouracil shows mutagenic potential (various strains of Salmonella typhimurium, micronucleus test in mice, at high concentrations chromosome strand damage in hamster fibroblasts). In vivo in male rats, chromosome aberrations and altered spermatogenesis and even infertility were observed. In female rats, fluorouracil reduced fertility and induced chromosome aberrations in the embryos. The effects in rabbits were less substantial.
Antimetabolites in animal studies revealed carcinogenic properties. However the risk of secondary tumours in humans seems to be lower than with alkylating substances.
