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Irinotecan hydrochloride, also known as CPT-11, is a chemotherapy medication belonging to the class of topoisomerase I inhibitors. It is widely used in the treatment of various types of cancer, particularly in colorectal cancer where it has demonstrated significant efficacy. This drug works by inhibiting the enzyme topoisomerase I, which is essential for DNA replication and repair in cancer cells. By disrupting the normal functioning of this enzyme, it interferes with the ability of cancer cells to divide and grow, ultimately leading to their death. Administration is typically done through intravenous infusion, allowing the drug to enter the bloodstream and distribute throughout the body. Its use is often combined with other chemotherapeutic agents or followed by a drug like leucovorin to enhance its effectiveness and reduce certain side effects.
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Chemical Formula |
C33H39ClN4O6 |
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Exact Mass |
622.26 |
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Molecular Weight |
623.15 |
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m/z |
622.26 (100.0%), 623.26 (35.7%), 624.25 (32.0%), 625.26 (11.4%), 624.26 (6.2%), 626.26 (2.0%), 623.25 (1.5%), 624.26 (1.2%) |
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Elemental Analysis |
C, 63.61; H, 6.31; Cl, 5.69; N, 8.99; O, 15.40 |
Irinotecan hydrochloride, a potent chemotherapeutic agent, is primarily utilized in the treatment of metastatic colorectal cancer, both as a monotherapy and in combination with other drugs such as fluorouracil and leucovorin. Its active metabolite, SN-38, inhibits topoisomerase I, disrupting DNA replication and inducing cell death in tumor cells. Irinotecan has demonstrated improved survival rates and disease control in patients with advanced colorectal cancer, making it a valuable addition to the oncologist's armamentarium. Its application is guided by careful monitoring of hematological and gastrointestinal toxicities to ensure safe and effective treatment.
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pharmacological effects
- Mechanism of Action: It and its active metabolite, SN-38, bind to the topoisomerase I-DNA complex, preventing the re-ligation of single-strand breaks that occur during DNA replication. This blockade disrupts DNA replication and repair processes, leading to cell death.
- Time-Dependent Cytotoxicity: The cytotoxicity and SN-38 is time-dependent and specifically targets cells in the S (synthesis) phase of the cell cycle, where DNA replication occurs.
- Metabolic Pathway: It is metabolized by carboxylesterase enzymes in vivo, primarily in the liver, to form its active metabolite SN-38. SN-38 is further converted to glucuronide conjugates for excretion.
- Enhanced Activity of SN-38: SN-38 exhibits greater potency and cytotoxicity than itself, with higher affinity for topoisomerase I and stronger inhibitory effects.
- In Vitro and In Vivo Studies: Its metabolites have demonstrated broad-spectrum antitumor activity in vitro against various human tumor cell lines and in vivo in preclinical models of various solid tumors.
- Resistance Profile: Importantly, it and SN-38 retain efficacy against tumor cells that express multidrug resistance proteins, such as P-glycoprotein (P-gp), indicating their potential use in overcoming chemotherapy resistance.
- Primary Indication: Based on its mechanism of action and antitumor activity, it is approved for the treatment of metastatic colorectal cancer, either as monotherapy or in combination with other chemotherapeutic agents.
- Efficacy and Tolerability: Clinical studies have shown that it based regimens can improve survival rates and response rates in patients with metastatic colorectal cancer, albeit with manageable side effects that require careful monitoring and management.
The main dose limiting toxicity of this product is delayed diarrhea and neutropenia.
1. Delayed diarrhea
The incidence rate is 80% to 90%, with severe cases accounting for 39%. The median occurrence time is 5 days after medication, with an average duration of 4 days, and severe cases can be fatal. Diarrhea that occurs 24 hours after medication should be considered as delayed diarrhea. Once the first watery stool or abnormal intestinal peristalsis occurs in the abdomen, loperamide should be taken orally immediately. The first dose is 4mg, followed by 2mg every 2 hours for at least 12 hours until the last watery stool. The most commonly used medication should not exceed 48 hours. If diarrhea persists after 48 hours, prophylactic oral broad-spectrum antibiotics (quinolones) should be started for 7 days, and other antidiarrheal treatments should be switched.
3. Other conditions such as acetylcholine syndrome
This includes "early" diarrhea (occurring within 24 hours), sweating, increased saliva, visual impairment, spasmodic diarrhea, and tearing. If the above symptoms are severe, atropine 0.25mg can be administered subcutaneously. The first cycle does not advocate prophylactic use of atropine, but if severe symptoms, including early diarrhea, prophylactic subcutaneous injection of atropine 0.25mg can be administered in the next cycle. Mucosal inflammation, hair loss, fatigue, and skin toxicity are all relatively mild.
4. Impact on liver function
In patients without progressive liver metastasis treated with monotherapy, the incidence of transient, mild to moderate elevation of serum levels of aminotransferase, alkaline phosphatase, and bilirubin was 9.2%, 8.1%, and 1.8%, respectively. 7.3% of patients experienced transient mild to moderate elevation of serum creatinine levels; In patients without progressive liver metastasis undergoing combination therapy, temporary (grade 1 and 2) AST ALT, The incidence of elevated levels of alkaline phosphatase or bilirubin is 15%, 11%, 11%, and 10%, respectively. The incidence of temporary 3-degree elevation is 0%, 0%, 0%, and 1% in patients, respectively. No 4-degree increase was observed.
2. Severe neutropenia
The incidence rate was 39.6%. Gastrointestinal reactions (nausea, vomiting) are common, but not severe. Prophylactic use of non gefitin (G-CSF) or saxagliptin (GM-CSF) is not recommended for neutropenia. If severe delayed neutropenia occurs in the first week, application may be considered.
Irinotecan hydrochloride, commonly known as CPT-11, is a chemotherapeutic agent used primarily in the treatment of colon and rectal cancers. Its safety profile is critical in assessing its suitability for use in patients. The following is a detailed overview of the safety considerations:
a. Hematological Toxicity:
- Neutropenia: Neutropenia is the most significant dose-limiting toxicity of it. It is reversible and non-cumulative, with a median nadir time of 8 days after administration. In monotherapy, severe neutropenia (neutrophil count < 500/mm³) occurs in approximately 22.6% of patients.
- Thrombocytopenia: Less common, with approximately 0.9% of patients experiencing platelet counts ≤ 50,000/mm³.
- Anemia: Although less severe, anemia can occur and should be monitored.
b. Gastrointestinal Toxicity:
- Delayed Diarrhea: Delayed diarrhea (occurring more than 24 hours after administration) is a dose-limiting toxicity. In monotherapy, approximately 20% of patients experience severe diarrhea.
- Nausea and Vomiting: Severe nausea and vomiting occur in approximately 10% of patients in monotherapy and are less frequent in combination therapy.
- Other Gastrointestinal Effects: Constipation, abdominal pain, anorexia, mucositis, and rarely, intestinal obstruction, bleeding, or perforation can occur.
c. Non-Hematological Toxicity:
- Acetylcholine Syndrome: A rare but potential side effect characterized by excessive tearing, sweating, salivation, blurred vision, and abdominal pain.
- Neurological: Rarely, patients may experience confusion, dizziness, or seizures.
- Other: Fatigue, alopecia (hair loss), and mild skin reactions are common.
- Dose Reductions: Dose reductions are recommended for patients experiencing severe neutropenia, neutropenia with fever or infection, or severe diarrhea requiring intravenous hydration.
- Monitoring: Regular blood counts and clinical assessments are necessary to monitor for toxicity and adjust the dose accordingly.
- It is contraindicated in patients with chronic inflammatory bowel disease or obstruction, severe bone marrow dysfunction, and in pregnant or lactating women.
- It should not be used in patients with bilirubin levels exceeding 1.5 times the upper limit of normal due to increased risk of severe neutropenia.
- Elderly Patients: Dose selection should be cautious in the elderly due to the potential for decreased physiological function.
- Renal Impairment: The use in patients with renal impairment has not been studied extensively, and caution is advised.
- Hepatic Impairment: Dose adjustments are necessary for patients with hepatic impairment, as increased bilirubin levels correlate with an increased risk of severe neutropenia.
- It can interact with other medications, particularly those that affect the metabolism of irinotecan or its active metabolite, SN-38.
- Close monitoring and potential dose adjustments may be necessary when irinotecan is administered with other chemotherapeutic agents or medications that can alter its pharmacokinetics.
synthesis Method
Preparation of 4-Piperidinopiperidine Carbonate:
- 4-Piperidinopiperidine is reacted with dimethyl carbonate in a dipolar aprotic solvent to form 4-piperidinopiperidine carbonate.
- This step establishes the basic piperidine structure needed for further modification.
Reaction with 7-Ethyl-10-Hydroxycamptothecin:
- The 4-piperidinopiperidine carbonate is then reacted with 7-ethyl-10-hydroxycamptothecin in a nonpolar solvent to yield irinotecan as the free base.
- This step introduces the camptothecin moiety, a key pharmacophore for the anticancer activity.
Conversion to Hydrochloride Salt:
- The irinotecan free base is dissolved in water and the pH is adjusted to 3–4 using hydrochloric acid.
- An excess of acetone (typically 4 times the volume of water) is added to precipitate the hydrochloride salt.
- The resulting crystals are filtered, washed, and vacuum-dried to obtain irinotecan hydrochloride.
Irinotecan Hydrochloride (Salicylic Acid Irinotecan) is a water-soluble semi-synthetic camptothecin derivative. Its chemical name is (+)-(4S)-4,11-Diethyl-4-hydroxy-9-[(4-piperidinylpiperidine) carbonyl]-1H-pyran-2-ylindolizine-3,14-(4H,12H)-dione hydrochloride trihydrate, with the molecular formula of C₃₃H₃₈N₄O₆·HCl·3H₂O and a molecular weight of 677.19. As a topoisomerase I inhibitor, its chemical properties are closely related to its anti-tumor activity.
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Physical State and Stability
Irinotecan hydrochloride appears as a pale white or light yellow powder at room temperature and is hygroscopic. It should be stored in a sealed container under low temperature (2-8℃) and a dry environment. Its melting point range is 250-256℃. It may decompose at high temperatures, indicating limited thermal stability. The compound is chemically stable at normal temperature and pressure, but it should be avoided from contact with strong oxidants to prevent oxidation reactions. It has significant water solubility and can be completely dissolved in water, slightly soluble in chloroform and ethanol, and almost insoluble in acetone and ether. This solubility characteristic is closely related to the polar groups in its molecule (such as hydroxyl and amino groups).
Acidity and Reactivity
As a salt of hydrochloric acid, irinotecan hydrochloride dissociates hydrogen ions (H⁺) in water, presenting acidity. The piperidine ring and hydroxyl groups in its molecule can participate in acid-base reactions, such as reacting with bases to form corresponding salts. In the body, irinotecan hydrochloride is converted into the active metabolite SN-38 through the action of carboxylic acid esterase (CES1, CES2) and butyrylcholinesterase (hBChE). This conversion process relies on the hydrolysis reaction of the ester bond in the molecule, demonstrating its reactivity. Additionally, the conjugated double bond and phenolic hydroxyl groups in the SN-38 molecule can participate in redox reactions, further influencing its efficacy and toxicity.
Mechanism of Topoisomerase I Inhibition
The core chemical property of irinotecan hydrochloride lies in its role as a topoisomerase I inhibitor. Topoisomerase I, during DNA replication and transcription, cuts single-stranded DNA and re-attaches it, alleviating the tension of DNA supercoiling. Irinotecan and its active metabolite SN-38 can stabilize the cleavable complex formed by topoisomerase I and DNA, preventing the re-connection of DNA single strands, resulting in DNA double-strand breaks. These breaks are irreparable and ultimately trigger cell apoptosis. This mechanism is closely related to the camptothecin backbone in its molecule - this backbone can insert into the large groove of DNA and interfere with the interaction between topoisomerase I and DNA.
Correlation between Metabolism and Efficacy
The metabolic process of irinotecan in the body significantly affects its efficacy and toxicity. Approximately 2-5% of the original drug is converted into SN-38 in the liver and plasma, and the latter is 100-1000 times more active than the original drug. SN-38 further combines with glucuronic acid to form SN-38G, reducing toxicity. However, in patients with UGT1A1 gene polymorphism, the generation of SN-38G is reduced, leading to the accumulation of SN-38 and causing severe neutropenia and diarrhea. This metabolic characteristic is closely related to the glucuronic acid binding site in its molecule, demonstrating the correlation between chemical properties and efficacy.
Safety and Toxicity Mechanisms
The toxicity of irinotecan hydrochloride is directly related to its chemical properties. The delayed diarrhea it causes results from the damage to intestinal epithelial cells by SN-38, leading to electrolyte imbalance and increased secretion. Acute cholinergic syndrome is associated with acetylcholinesterase inhibition, presenting symptoms such as abdominal pain, salivation, and tearing. Additionally, the oxidative metabolites of SN-38 can cause hepatotoxicity, manifested as elevated transaminases and bilirubin levels. These toxic reactions are closely related to the metabolites of the active groups in its molecules, such as phenolic hydroxyl groups and ester bonds.
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