Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany
Pharmacotherapeutic group: Alkylating agents
ATC code: L01AX04
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.
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.
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).
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.
Because of its pharmacodynamic properties dacarbazine shows mutagenic, carcinogenic and teratogenic effects which are detectable in experimental test systems.
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