Busulfan Advanced Drug Monograph

Busulfan Report

Name: Busulfan Name (English): Busulfan DrugBank ID: DB01008 Type: Small Molecule CAS Number: 55-98-1

Description: Busulfan is an alkylating agent used primarily in the treatment of chronic myelogenous leukemia and as part of conditioning regimens before hematopoietic stem cell transplantation for various hematologic malignancies and non-malignant diseases. It works by alkylating DNA, which disrupts DNA replication and RNA transcription, ultimately leading to cell death.

Pharmacodynamics: Busulfan is a bifunctional alkylating agent that forms DNA crosslinks, mainly guanine-adenine intrastrand crosslinks, interfering with DNA replication and RNA transcription. This non-specific action affects both cancerous and normal cells, particularly hematopoietic progenitor cells.

Pharmacokinetics:

• Absorption: Well absorbed from the gastrointestinal tract, with an absolute bioavailability of approximately 80%. Peak plasma concentrations are reached within approximately 0.9 hours.
• Distribution: Highly lipophilic and crosses the blood-brain barrier.
• Metabolism: Extensively metabolized in the liver, primarily by conjugation with glutathione via glutathione S-transferases (GSTs), with GSTA1 being the primary isoform.
• Elimination: Metabolites are excreted in the urine.

Indications:

• Palliative treatment of chronic myelogenous leukemia.
• Conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.
• Component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases.

Contraindications:

• Hypersensitivity to busulfan.
• Severe bone marrow depression.

Adverse Effects: Common adverse effects include nausea, vomiting, diarrhea, anorexia, and skin hyperpigmentation. Serious adverse effects can include bone marrow suppression (myelosuppression), pulmonary toxicity (busulfan lung), hepatic veno-occlusive disease, seizures, and secondary malignancies. Busulfan is also a known carcinogen.

Drug Interactions: Busulfan can interact with other myelosuppressive agents, increasing the risk of hematologic toxicity. It can also interact with drugs affecting hepatic metabolism, such as cytochrome P450 enzyme inducers and inhibitors, and with drugs that affect glutathione levels.

Mechanism of Action: Busulfan's mechanism of action involves the alkylation of DNA by forming carbonium ions after hydrolysis of its methanesulfonate groups. These carbonium ions alkylate DNA bases, leading to DNA crosslinks, particularly guanine-adenine intrastrand crosslinks. This DNA damage inhibits DNA replication and RNA transcription, ultimately causing cell cycle arrest and apoptosis.

Chemical Formula: $\text{C}6\text{H}{14}\text{O}_6\text{S}_2$ Molecular Weight: 246.302 g/mol

Synonyms:

• 1,4-Bis(methanesulfonoxy)butane
• 1,4-Butanediol dimethanesulfonate
• 1,4-Dimesyloxybutane
• Busulphan
• Myleran