Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alkylating agents, ATC code: L01AX04.

Mechanism of action
Dacarbazine is a cytostatic agent. The antineoplastic effect is due to an inhibition of cell growth which is independent of the cell cycle and due to an inhibition of DNA synthesis. An alkylating effect has also been shown and other cytostatic mechanisms may also be influenced by dacarbazine.

Dacarbazine is considered not to show an antineoplastic effect by itself. However, by microsomal N- demethylation it is quickly converted to 5-amino-imidazole-4-carboxamide and a methyl cation, which is responsible for the alkylating effect of the medicinal product.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Distribution
After intravenous administration dacarbazine is quickly distributed into tissue. Plasma protein binding is 5 %.
Kinetics in plasma are biphasic; the initial (distribution) half -life is only 20 minutes, terminal half -life is 0.5 - 3.5 hours.

Biotransformation

Dacarbazine is inactive until metabolised in the liver by cytochromes P450 to form the reactive N- demethylated species HMMTIC and MTIC. This is catalysed by CYP1A1, CYP1A2, and CYP2E1.
MTIC is further metabolised to 5-aminoimidazole-4-carboxamide (AIC).

Elimination
Dacarbazine is metabolised mainly in the liver by both hydroxylation and demethylation, approx. 20 – 50 % of the medicinal product is excreted unmodified by the kidney via renal tubular secretion.