BUSULFAN

Chemistry - An alkylsulfonate antineoplastic agent, busulfan occurs as white, crystalline powder. Itis slightly soluble in alcohol and very slightly soluble in water.

Storage, Stability, Compatibility

Busulfan tablets should be stored in well-closed containers atroom temperature.

Pharmacology - BUSULFAN

Busulfan is a bifunctional alkylating agent antineoplastic and is cel cycle-phasenonspecific. The exact mechanism of action has not been determined, but is thought to be due to itsalkylating, cross-linking of strands of DNA and myelosuppressive properties. Busulfan's primaryactivity is against cells of the granulocytic series.

Uses, Indications

Busulfan may be useful in the adjunctive therapy of chronic granulocyticleukemias in small animals.

Pharmacokinetics - BUSULFAN

Busulfan is well absorbed after oral administration. Distribution characteristics are not well described and it is unknown whether the drug enters the CSF, brain or maternalmilk. Busulfan is rapidly hepatically metabolized to at least 12 different metabolites that are slowlyexcreted into the urine. In humans, serum half life of busulfan averages about 2.5 hours.

Contraindications, Precautions, Reproductive Safety

Busulfan is contraindicated in patientswho have shown resistance to the drug in the past. It should only be used by veterinarians with theexperience and resources to monitor the toxicity of this agent. The risk versus benefits of therapymust be carefully considered in patients with preexisting bone marrow depression or concurrentinfections. Additive bone marrow depression may occur in patients undergoing concomitantradiation therapy.
Busulfan's teratogenic potential has not been well documented, but it is mutagenic in mice andmay potentially cause a variety of fetal abnormalities. It is generally recommended to avoid the drugduring pregnancy, but because of the seriousness of the diseases treated with busulfan, the potentialbenefits to the mother must be considered.

Adverse Effects, Warnings

The most commonly associated adverse effect seen with busulfantherapy is myelosuppression. In humans, anemia, leukopenia, and thrombocytopenia may all benoted. Onset of leukopenia is generally 10 to 15 days after initiation of therapy and leukocytenadirs occurring on average around 11-30 days. Severe bone marrow depression can result inpancytopenia that may take months to years for recovery. In humans, bronchopulmonary dysplasiawith pulmonary fibrosis, uric acid nephropathy, and stomatitis have been reported. These effects aremore uncommon and generally associated with chronic, higher dose therapy.

Overdosage, Acute Toxicity

There is limited experience with busulfan overdoses. The LD50 inmice is 120 mg/kg. Chronic overdosage is more likely to cause serious bone marrow suppression, than is an acute overdose. However, any overdose, should be treated seriously with standard gutemptying protocols used when appropriate and supportive therapy initiated when required. There isno known specific antidote for busulfan intoxication.

Drug Interactions

Concurrent use with other bone marrow depressant medications may result in additive myelosuppression. Thioguanine and busulfan used concomitantly may result in hepatotoxicity.
Laboratory Considerations - Busulfan may raise serum uric acid levels. Drugs such as allopurinol may be required to control hyperuricemia.