Pharmacology: Pharmacodynamics: The exposure-response relationship for efficacy or safety is unknown.
Mechanism of Action: The mechanism of action of carmustine is not fully understood. While carmustine alkylates DNA and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. The metabolites may contribute to antitumor activity and toxicities of carmustine.
Pharmacokinetics: Distribution: Carmustine crosses the blood-brain barrier. Levels of radioactivity in the CSF are greater than or equal to 50% of those measured concurrently in plasma.
Elimination: Following a short intravenous infusion, the reported elimination half-life ranges from 15 minutes to 75 minutes.
Metabolism: Carmustine may be inactivated through denitrosation reactions catalyzed by both cytosolic and microsomal enzymes, including NADPH and glutathione-S-transferase.
Excretion: Approximately 60% to 70% of a total dose is excreted in the urine within 96 hours. Approximately 10% is eliminated as respiratory CO2.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carmustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans [see Adverse Reactions].
Carmustine was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.
Male rats treated with carmustine at cumulative doses ≥36 mg/kg (216 mg/m2), approximately 0.15 times the maximum cumulative human dose on a mg/m2 basis, showed decreases in reproductive potential when mated with untreated female rats (e.g., decreased implantations, increased resorption rate, and a decrease in viable fetuses).