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Busulfan | CAS No: 55-98-1 | GMP-certified suppliers
A medication that supports conditioning regimens before allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia, acute myeloid leukemia, and select nonmalignant diseases.
Therapeutic categories
Primary indications
- For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use)
- It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases
Product Snapshot
- Busulfan is available as an oral tablet and intravenous solution formulation
- It is primarily used in conditioning regimens prior to hematopoietic progenitor cell transplantation for chronic myelogenous leukemia, acute myeloid leukemia, and nonmalignant diseases
- Busulfan has regulatory approval in the US, EU, and Canada
Clinical Overview
Pharmacologically, busulfan belongs to the class of alkylating agents, specifically organosulfonic acid esters. It exerts antineoplastic effects by forming covalent bonds with DNA. Upon hydrolysis, busulfan releases reactive carbonium ions that alkylate DNA, predominantly producing guanine-adenine intrastrand crosslinks. These crosslinks interfere with DNA replication and RNA transcription by preventing DNA strand separation necessary for cell division. Since these alkylation-induced lesions cannot be repaired by cellular mechanisms, affected cells undergo apoptosis. Busulfan’s alkylation mechanism is cell cycle-nonspecific and results in myelosuppression, underlying its potent immunosuppressive effect on bone marrow.
Busulfan is metabolized primarily in the liver, with a narrow therapeutic index. It is known to be a substrate of cytochrome P450 enzymes including CYP3A4, which may influence its pharmacokinetics and drug interaction profile. Resistance to busulfan has been associated with overexpression of glutathione S-transferase MGST2, although the precise metabolic role remains unclear.
The safety profile of busulfan necessitates caution due to its myelosuppressive and cardiotoxic potential, as well as its classification as a known carcinogen per the National Toxicology Program. Close monitoring of hematologic parameters is essential during therapy.
From an API sourcing and quality perspective, busulfan requires stringent control of purity and residual solvent levels given its narrow therapeutic window and cytotoxicity. Suppliers should provide comprehensive certificates of analysis demonstrating compliance with pharmacopeial standards. Stability considerations during storage and handling must also be evaluated to preserve API integrity.
Identification & chemistry
| Generic name | Busulfan |
|---|---|
| Molecule type | Small molecule |
| CAS | 55-98-1 |
| UNII | G1LN9045DK |
| DrugBank ID | DB01008 |
Pharmacology
| Summary | Busulfan is an alkylating agent that exerts its antineoplastic effects by forming guanine-adenine DNA intrastrand crosslinks through alkylation, disrupting DNA replication and transcription. This DNA damage prevents cellular division and induces apoptosis, acting in a cell cycle-nonspecific manner. Busulfan is primarily used in conditioning regimens prior to hematopoietic progenitor cell transplantation. |
|---|---|
| Mechanism of action | 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. |
| Pharmacodynamics | 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. |
Targets
| Target | Organism | Actions |
|---|---|---|
| DNA | Humans | cross-linking/alkylation |
ADME / PK
| Absorption | 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 |
| Protein binding | 32% bound to plasma proteins and 47% bound to red blood cells. |
| Metabolism | Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity. |
| Route of elimination | 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. |
| 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] |
Formulation & handling
- Busulfan is available for both oral and intravenous administration, requiring formulation flexibility for solution concentrates and coated tablets.
- As a small molecule with moderate water solubility and low logP, it is suitable for injectable solutions but may require careful solvent selection to maintain stability.
- Monitoring for potential interactions with grapefruit and St. John's Wort is advised to avoid variability in bioavailability.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient's primary patent expired in the United States on March 30, 2014, allowing for generic competition in the US, EU, and Canadian markets where the product is currently marketed. The product is in a mature market phase with established availability across these regions. |
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| Markets | EU, US, Canada |
|---|
Supply Chain
| Supply chain summary | Busulfan is manufactured by multiple originator companies, including Otsuka Pharmaceutical Co. Ltd and GlaxoSmithKline, with packaging handled by GlaxoSmithKline Inc., Otsuka America, and PDL BioPharma Inc. Branded products are present across major markets including the US, EU, and Canada. The primary patent listed expired in 2014, indicating that generic competition is likely established or forthcoming in these regions. |
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Safety
| 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. |
|---|
- Handle with appropriate protective equipment due to potential for severe hematologic toxicity upon exposure or overdose
- Avoid inhalation and skin contact to minimize risk of systemic adverse effects including respiratory and neurological symptoms
- Monitor for signs of toxicity such as unusual bleeding, fatigue, or respiratory distress during manufacturing or handling processes
Busulfan is a type of Alkylating agents
Alkylating agents are a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that play a significant role in cancer treatment. These compounds possess the ability to attach alkyl groups to the DNA molecule, effectively disrupting its structure and preventing cell replication. This mechanism of action makes alkylating agents potent chemotherapy drugs for various types of cancers.
Alkylating agents are often classified based on their chemical structure, which includes nitrogen mustards, ethylenimines, nitrosoureas, and alkyl sulfonates, among others. Each subclass exhibits unique chemical properties and therapeutic applications. For instance, nitrogen mustards like cyclophosphamide and mechlorethamine are used to treat lymphomas and leukemia, while nitrosoureas such as carmustine and lomustine are effective against brain tumors.
The alkylating agents' mode of action involves the transfer of alkyl groups to cellular components, primarily DNA. This leads to the formation of DNA adducts, cross-links, and DNA strand breaks, ultimately hindering DNA replication and causing cell death. The indiscriminate nature of alkylating agents can also affect healthy cells, leading to various side effects such as bone marrow suppression and gastrointestinal disturbances.
Despite their potential side effects, alkylating agents remain valuable tools in cancer therapy due to their broad spectrum of activity against different types of tumors. Ongoing research focuses on developing more selective and targeted alkylating agents to improve their therapeutic index and minimize adverse effects. The use of alkylating agents in combination with other chemotherapy drugs or radiation therapy is also being explored to enhance treatment outcomes and reduce drug resistance.
In conclusion, alkylating agents are an essential subclass of pharmaceutical APIs widely employed in cancer treatment. Their ability to disrupt DNA structure and impede cell replication makes them effective against various types of tumors, although careful management of side effects is necessary. Ongoing advancements and research continue to refine their therapeutic potential in the fight against cancer.
Busulfan (Alkylating agents), classified under Anticancer drugs
Anticancer drugs belong to the pharmaceutical API (Active Pharmaceutical Ingredient) category designed specifically to combat cancer cells. These powerful medications play a crucial role in cancer treatment and are developed to target and destroy cancerous cells, preventing their growth and spread.
Anticancer drugs are classified based on their mode of action and can include various types such as chemotherapy drugs, targeted therapy drugs, immunotherapy drugs, and hormonal therapy drugs. Chemotherapy drugs work by interfering with the cell division process, thereby inhibiting the growth of cancer cells. Targeted therapy drugs, on the other hand, are designed to attack specific molecules or genes involved in cancer growth, minimizing damage to healthy cells. Immunotherapy drugs stimulate the body's immune system to recognize and destroy cancer cells. Hormonal therapy drugs are used in cancers that are hormone-dependent, such as breast or prostate cancer, to block the hormones that fuel cancer cell growth.
These APIs are typically synthesized through complex chemical processes in state-of-the-art manufacturing facilities. Stringent quality control measures ensure the purity, potency, and safety of these drugs. Anticancer APIs undergo rigorous testing and adhere to stringent regulatory guidelines before being approved for clinical use.
Due to their critical role in cancer treatment, anticancer drugs are in high demand worldwide. Researchers and pharmaceutical companies continually strive to develop new and more effective APIs in this category to enhance treatment outcomes and minimize side effects. The ongoing advancements in the field of anticancer drug development offer hope for improved cancer therapies and better patient outcomes.
Busulfan API manufacturers & distributors
Compare qualified Busulfan API suppliers worldwide. We currently have 7 companies offering Busulfan API, with manufacturing taking place in 5 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Cambrex | Producer | Italy | United States | CoA, GMP | 104 products |
| ChemPacific | Producer | United States | Unknown | CoA, USDMF | 10 products |
| Emcure Pharma | Producer | India | India | CEP, CoA, FDA, GMP, USDMF, WC | 80 products |
| Farmabios | Producer | Italy | Italy | CoA, GMP, ISO9001, USDMF | 58 products |
| KRKA | Producer | Slovenia | Slovenia | CoA, GMP | 81 products |
| Shilpa Medicare Ltd | Producer | India | India | BSE/TSE, CEP, CoA, GMP, ISO9001, MSDS, USDMF, WC | 54 products |
| Shivalik Rasayan Ltd. | Producer | India | India | CEP, CoA, GMP, USDMF, WC, WHO-GMP | 13 products |
When sending a request, specify which Busulfan API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
Use the list above to find high-quality Busulfan API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
