Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, Antimetabolites, Pyrimidine analogues, ATC code: L01BC01

Alexan contains cytarabine (4-amino-1- (β-D-arabinofuranosyl) -1 H-pyrimidin-2-one), a cytostatic agent belongs to the antimetabolite group. It differs from the body’s own pyrimidine nucleoside 
cytidine and 2’-deoxycytidine only in the sugar residue (arabinose instead of ribose), that is, it is a pyrimidine analogue.

The active cytarabine nucleotides inhibit DNA synthesis in the S-phase of the cell cycle. The proposed molecular mechanisms of action for this effect are inhibition of cytidine phosphate reductase, incorporation into DNA and RNA leading to the dysfunction of these nucleic acids and inhibition of DNA polymerase. In particular, the virally-induced RNA-dependent DNA polymerase (reverse transcriptase) is strongly inhibited. The ability of cytarabine to recruit resting cells (G 0 phase) into the proliferation cycle, making these cells susceptible to the chemotherapeutic effect of cell phase-specific cytostatic agents, probably contributes to the cytostatic effect of cytarabine.

The susceptibility of a tissue to cytarabine is dependent on the relationship between its cytidine deaminase and cytidine kinase activity. In the course of treatment with cytarabine, both pre-existing and acquired resistance to this cytotoxic agent is observed, which is attributed to the ratio of the said enzymes in the tumour tissue.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Following uptake into the cells via the pyrimidine nucleoside transport mechanism, cytarabine is deaminated into the inactive uracil arabinoside on the one hand and phosphorylated into the active nucleotide on the other hand (cytarabine mono-, di- and triphosphate).

The pharmacokinetic properties of cytarabine are determined by its high water solubility and its low lipid solubility. The medicinal product is to be administered parenterally. After the initial distribution phase, the plasma level decreases with a half-life of 2−2.5 hours. In this second phase of elimination, about 80% is in the form of the inactive uracil arabinoside. Within 24 hours, 80% of the administered dose is eliminated through urine, predominantly in the form of uracil arabinoside. In cerebrospinal fluid, the concentrations of cytarabine following intravenous administration are, as a rule, 40% of those in blood plasma. In intrathecal administration, the level of cytarabine in cerebrospinal fluid decreases with a half-life of 2−11 hours, whereby, due to the lower deaminase activity in cerebrospinal fluid, predominantly unchanged cytarabine is available.

The kinetics of cytarabine blood levels remain constant following repeated administration and are not affected by corticosteroids and other cytostatics.

In IV infusion, a constant, dose-dependent blood levels are achieved after 30−60 minutes.

Following subcutaneous administration, peak plasma levels are achieved after 20−60 minutes. At comparable doses, they are markedly lower than plasma levels achievable by intravenous administration.