Pharmacology: Pharmacodynamics: Mechanism of action: The precise mechanism(s) of action of dacarbazine has not been determined but it appears that the drug exerts its cytotoxic effect by acting as an alkylating agent. Dacarbazine is probably not a cell cycle-phase specific agent; it exhibits no specific dose-response relationship or schedule dependency. The drug possesses minimal immunosuppressive activity.
Pharmacokinetics: Absorption: Dacarbazine is poorly and erratically absorbed from the gastrointestinal tract, which could result in unpredictable tumour responses and possible increased toxicity. Therefore, the drug is recommended for intravenous administration only. Peak plasma concentrations of about 8 micrograms per mL are reached immediately following administration of dacarbazine 4.5 milligrams/kg by intravenous push.
Distribution: The volume of distribution of dacarbazine exceeds total body water content, suggesting localization in some body tissue, probably the liver. The drug is only slightly bound to plasma proteins. Dacarbazine crosses the blood-brain barrier to a limited extent; CSF concentrations are reported to be about 14% of plasma concentrations. It is not known if dacarbazine crosses the human placenta or distributes into milk.
Elimination: Plasma concentrations of dacarbazine appear to decline in a biphasic manner. In individuals with normal renal function, the half-life in the initial phase (t½α) average 19 minutes and the half-life in the terminal phase (t½β) averages 5 hours. The manufacturer states that in one patient with renal and hepatic dysfunction, the t½α was 55 minutes and the t½β was 7.2 hours.
Dacarbazine is extensively metabolized. Dacarbazine is N-demethylated by liver microsomal enzymes to 5-(3-monomethly-1-triazenyl)-1H-imidazole-4-carboxamide (MIC) which spontaneously decomposes to form AIC plus an unidentified alkylating or methylating moiety. Small amounts of the drug may also be converted to the diazonium salt of AIC (Diazo-ICA), which undergoes spontaneous intramolecular coupling to form 2-azahypoxanthine. Some dacarbazine metabolites may contribute to the antineoplastic effect of the drug. Metabolism of dacarbazine may be enhanced by agents such as phenobarbital and phenytoin which induce liver microsomal enzymes.
Dacarbazine is excreted in the urine by tubular secretion; 30-46% of an administered dose is excreted in the urine within 6 hours. About half of the drug excreted is recovered as unchanged dacarbazine and half as AIC.