Busulfan

Busulfan Uses, Dosage, Side Effects, Food Interaction and all others data.

Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.

Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however.

Busulfan
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Busulfan
Availability	Prescription only
Generic	Busulfan
Busulfan Other Names	1,4-Dimesyloxybutane, Busulfan, Busulfano, Busulfanum, Busulphan
Related Drugs	fluconazole, Diflucan, hydroxyurea, cisplatin, cyclophosphamide, Gleevec, filgrastim, Sprycel, Zarxio, Tasigna
Weight	6mg/ml, 2mg
Type	Tablet, Intravenous, Intravenous Solution, Oral Tablet, Oral/injection
Formula	C₆H₁₄O₆S₂
Weight	Average: 246.302 Monoisotopic: 246.02317956
Protein binding	32% bound to plasma proteins and 47% bound to red blood cells.
Groups	Approved, Investigational
Therapeutic Class	Cytotoxic Chemotherapy
Manufacturer	Chandra Bhagat Pharma Pvt Ltd, Aspen
Available Country	India, United Kingdom, United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Busulfan is used for Chronic myeloid leukaemia, Polycythemia vera, Essential thrombocythemia, Conditioning regimens for bone marrow transplantation, Conditioning regimens for bone marrow transplantation

Busulfan is also used to associated treatment for these conditions: Essential Thrombocythemia (ET), Polycythemia Vera (PV), Chronic Chronic myelogenous leukemia, Conditioning regimens for allogeneic stem cell transplantation therapy

How Busulfan works

Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. These crosslinks occur through a SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis.

Dosage

Busulfan dosage

Polycythemia vera:

Adult:4-6 mg daily continued for 4-6 wk withblood count monitoring, particularly platelet. Further courses may be given if relapse occurs; alternatively, a maintenance therapy approx half the induction dose may be given.

Chronic myeloid leukaemia:

Adult:Remission induction: Initially, 0.06 mg/kg daily. Max: 4 mg daily. May increase dose if response is inadequate after 3 wk. Continue until WBC count falls to 15,000-25,000 cells/mm3(usually 12-20 wk); may stop earlier if platelet count is <100,000 cells/mm3. Maintenance: If WBC count rises to 50,000 cells/mm3or symptoms return: Resume induction dose; if remission is <3 mth: 0.5-2 mg daily, given as continuous maintenance.
Child:Same as adult dose.

Essential thrombocythemia:

Adult:2-4 mg daily.

Side Effects

Bone marrow depression, manifested as leucopenia, thrombocytopenia and anaemia; hyperpigmentation, GI disturbances, impaired fertility and gonadal function. Rarely, dry skin, gynaecomastia, cataract formation, at high doses, CNS effects including convulsions.

Toxicity

Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness.

Precaution

Discontinue if lung toxicity develops. Severe hepatic or renal impairment. Pregnancy and lactation.

Interaction

Additive myelosuppression with other myelosuppressive agents. Cytotoxic agents may increase risk of pulmonary toxicity. May reduce response to vaccines, possibility of generalised infections with live vaccines. Increased risk of adverse effects if given in conjunction with or soon after radiotherapy. Decreased clearance when used wit cyclophosphamide, itraconazole or paracetamol. Combination with thioguanine may result in oesophageal varices, hepatotoxicity and portal HTN. Increased clearance by phenytoin.

Food Interaction

Drink plenty of fluids.
Exercise caution with grapefruit products.
Exercise caution with St. John's Wort.
Take at the same time every day.

Busulfan Drug Interaction

Unknown: arginine, arginine, levocarnitine, levocarnitine, cysteine, cysteine, lithium, lithium, valproic acid, valproic acid, cyanocobalamin, cyanocobalamin, pyridoxine, pyridoxine, cholecalciferol, cholecalciferol, phytonadione, phytonadione, menaquinone, menaquinone

Busulfan Disease Interaction

Major: infections, myelosuppressionModerate: cardiac tamponade, seizure disorders

Elimination Route

Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg.

Half Life

2.6 hours

Clearance

2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four days]

Elimination Route

Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk.

Contraindication

Patient with chronic myelogenous leukemia whose disease was resistant to prior therapy with the drug; definitive diagnosis of chronic myelogenous leukemia has not firmly established.