Arasid-100/Arasid-500/Arasid-1000 Mechanism of Action

Pharmacotherapeutic group: Pyrimidine analogue. ATC code: L01BC01.
Pharmacology: Pharmacodynamics: Cytarabine, a pyrimidine nucleoside analogue, is an antineoplastic agent, which inhibits the synthesis of deoxyribonucleic acid specifically in the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. Detailed studies on the mechanism of cytotoxicity in vitro suggests that the primary action of cytarabine is inhibition of deoxycytidine synthesis its active triphosphate metabolite arabinofuranosyl cytosine triphosphate ARA-CTP, although inhibition of cytidylic kinases and incorporation of the compound into nucleic acids may also play a role in its cytostatic and cytocidal actions.
High dose cytarabine regimens can overcome the resistance of leukemic cells no longer responding to conventional doses. Several mechanisms appear to be involved to this resistance: Increases in the quantity of substrate; Increase in the intracellular pool of ARA-CTP, since there is a positive correlation between intracellular retention of ARA-CTP and percentage of cells in S-phase.
Pharmacokinetics: Cytarabine is deaminated to arabinofuranosyl uracil in the liver and kidneys. After intravenous administration to humans, only 5.8% of the administered doses is excreted unaltered in urine within 12-24 hours, 90% of the dose is excreted as the inactive deaminated product, arabinofuranosyl uracil (ARA-U). Cytarabine appears to be metabolised rapidly, primarily by the liver and perhaps by the kidney. After single high intravenous doses, blood levels fall to unmeasurable levels within 15 minutes in most patients. Some patients have indemonstrable circulating drug as early as 5 minutes after injection. The half-life of the drug is 10 minutes.
High dose cytarabine achieves plasma peak levels 200 fold higher than that observed with conventional dose regimen. The peak of inactive metabolite ARA-U, with high dose regimen, is observed after only 15 minutes. The renal clearance is slower with high dose cytarabine than with conventional dose cytarabine. The cerebrospinal fluid (CSF) levels achieved, after high dose 1-3 g/m² cytarabine intravenous infusion, are around 100-300 nanograms/ml.
Peak plasma levels are achieved about 20-60 minutes after subcutaneous application. At comparable doses, they are significantly lower than plasma levels achieved after intravenous administration.
Toxicology: Preclinical safety data: There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.