Introduction

Busulfan, which can be given in both oral and IV dosage forms, is a chemotherapy drug that is primarily used as part of a conditioning/preparative regimen prior to bone marrow transplants to treat CML (chronic myeloid leukemia) and AML (acute myeloid leukemia) and other hematological malignancies. The preparative regiment serves to eradicate cancerous stem cells and residual hematopoiesis before bone marrow is transplanted. In addition, Busulfan is FDA-indicated for the palliative treatment of CML. Busulfan is also used off-label to treat breast cancer, multiple myeloma, and ovarian cancer.

Pharmacokinetics

Busulfan is highly lipophilic and easily crosses the cell membrane. It is extensively metabolized; less than 2% of it is excreted and renally unchanged. Membrane transporters for Busulfan have not been elucidated. Busulfan is primarily metabolized in the liver by glutathione s-transferases (GSTs). GSTA1 is the predominant GST isoform catalyzing busulfan metabolism, whereas GSTM1 and GSTP1 also play a role. The busulfan glutathione conjugate is then converted to a cysteine conjugate through the mercapturate pathway involving first -glutamyl transferase (GGT) and then dipeptidase/cysteinylglycinase (DPEP). The cysteine conjugate can subsequently undergo enzymatic -elimination mediated by cystathionine gamma-lyase (CTH), resulting in tetrahydrothiophene (THT), NH4+, and pyruvate. THT can then be oxidized by the cytochrome P450 (CYP) or flavin containing monooxygenase (FMO), forming additional metabolites sulfolane and 3-hydroxysulfolane. Alternatively, the cysteine conjugate can be acetylated by N-acetyltransferase (NAT).

Side effects

COMMON, SOME MAY BE SERIOUS. Of 100 people receiving Busulfan, more than 20 and up to 100 may have:

Anemia, which may require blood transfusions

Infection, especially when white blood cell count is low

Bruising, bleeding

Diarrhea, nausea, vomiting, loss of appetite

Sores in the mouth, which may cause difficulty swallowing

Belly pain

Headache

Difficulty sleeping

Worry

Fever

OCCASIONAL, SOME MAY BE SERIOUS. In 100 people receiving Busulfan, from 4 to 20 may have:

Seizure

Internal bleeding, which may cause coughing up blood

Damage to or scarring of the lungs

Damage to the liver, which may cause yellowing of eyes and skin, swelling

Menopause

RARE AND SERIOUS. In 100 people receiving Busulfan, 3 or fewer may have:

Fluid around the heart, which may cause shortness of breath

Cancer of bone marrow caused by chemotherapy

References

[1] Busulfan Pathway, Pharmacodynamics (pharmgkb.org) https://www.pharmgkb.org/pathway/PA165374494

[2] Busulfan - an overview | ScienceDirect Topics https://www.sciencedirect.com/topics/medicine-and-dentistry/busulfan