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药品详细

Paclitaxel(紫杉醇)

化学结构式图
中文名
紫杉醇
英文名
Paclitaxel
分子式
C47H51NO14
化学名
(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-1,9-dihydroxy-15-{[(2R,3S)-2-hydroxy-3-phenyl-3-(phenylformamido)propanoyl]oxy}-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0^{3,10}.0^{4,7}]heptadec-13-en-2-yl benzoate
分子量
Average: 853.9061
Monoisotopic: 853.330955345
CAS号
33069-62-4
ATC分类
L01C 植物碱和其他天然产物
药物类型
small molecule
阶段
approved
商品名
Abraxane (Abraxis Bioscience);Epitaxol;LipoPac;Onxol;Paxceed;Paxene;Taxol;Taxol A;Vascular Wrap;Xorane;
同义名
7-epi-Paclitaxel;7-epi-Taxol;7-Epipaclitaxel;7-Epitaxol;ABI-007;
基本介绍

A cyclodecane isolated from the bark of the Pacific yew tree, TAXUS brevifolia. It stabilizes microtubules in their polymerized form leading to cell death. [PubChem] ABI-007 (Abraxane) is the latest attempt to improve upon paclitaxel, one of the leading chemotherapy treatments. Both drugs contain the same active agent, but Abraxane is delivered by a nanoparticle technology that binds to albumin, a natural protein, rather than the toxic solvent known as Cremophor. It is thought that delivering paclitaxel with this technology will cause fewer hypersensitivity reactions and possibly lead to greater drug uptake in tumors.

生产厂家
  • Abraxis bioscience llc
  • Accord healthcare inc usa
  • Actavis totowa llc
  • Bedford laboratories div ben venue laboratories inc
  • Bristol myers squibb co pharmaceutical research institute
  • Ebewe pharma ges mbh nfg kg
  • Fresenius kabi oncology plc
  • Hospira inc
  • Mylan pharmaceuticals inc
  • Pliva lachema as
  • Teva parenteral medicines inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Wall ME, Wani MC: Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award Lecture. Cancer Res. 1995 Feb 15;55(4):753-60. Pubmed
  2. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT: Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971 May 5;93(9):2325-7. Pubmed
  3. Fuchs DA, Johnson RK: Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep. 1978 Aug;62(8):1219-22. Pubmed
  4. Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH, Humphrey RW, Feigal E, Steinberg SM, Broder S, et al.: Treatment of HIV-associated Kaposi’s sarcoma with paclitaxel. Lancet. 1995 Jul 1;346(8966):26-8. Pubmed
  5. ABI 007. Drugs R D. 2004;5(3):155-9. Pubmed
  6. Gaitanis A, Staal S: Liposomal doxorubicin and nab-paclitaxel: nanoparticle cancer chemotherapy in current clinical use. Methods Mol Biol. 2010;624:385-92. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Taxanes
Substructures
  • Taxanes
  • Carbonyl Compounds
  • Carboxylic Acids and Derivatives
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Benzyl Alcohols and Derivatives
  • Acetates
  • Benzoates
  • Amino Ketones
  • Short-chain Hydroxy Acids
  • Cyclobutane and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Benzoyl Derivatives
  • Cyclohexenes and Derivatives
  • Cyclooctane and Derivatives
  • Benzamides
  • Ketones
适应症
Cancer 癌症;
药理
Indication Used in the treatment of Kaposi's sarcoma and cancer of the lung, ovarian, and breast. Abraxane® is specfically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer.
Pharmacodynamics Paclitaxel is a taxoid antineoplastic agent indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary, and other various cancers including breast cancer. Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Mechanism of action Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.
Absorption I.V injected
Volume of distribution
  • 227 to 688 L/m2
Protein binding 89%-98%
Metabolism
Hepatic. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydrox-ypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6a, 3’-p-dihydroxypaclitaxel, by CYP3A4.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Paclitaxel
    		3'-p-hydroxypaclitaxel Details
    Paclitaxel
      		6a-hydrox-ypaclitaxel Details
      Paclitaxel
        		6a, 3'-p-dihydroxypaclitaxel Details
        Route of elimination In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine.
        Half life Average distribution half-life of 0.34 hours and an average elimination half-life of 5.8 hours.
        Clearance
        • 21.7 L/h/m2 [Dose 135 mg/m2, infusion duration 24 h]
        • 23.8 L/h/m2 [Dose 175 mg/m2, infusion duration 24 h]
        • 7 L/h/m2 [Dose 135 mg/m2, infusion duration 3 h]
        • 12.2 L/h/m2 [Dose 175 mg/m2, infusion duration 3 h]
        Toxicity Rat (ipr) LD50=32530 µg/kg. Symptoms of overdose include bone marrow suppression, peripheral neurotoxicity, and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity.
        Affected organisms
        • Humans and other mammals
        Pathways
        Pathway Name SMPDB ID
        Smp00434 Paclitaxel Pathway SMP00434
        理化性质
        Properties
        State solid
        Experimental Properties
        Property Value Source
        melting point 213-216 °C Not Available
        water solubility Insoluble Not Available
        logP 3 Not Available
        Predicted Properties
        Property Value Source
        water solubility 5.56e-03 g/l ALOGPS
        logP 3.2 ALOGPS
        logP 3.54 ChemAxon
        logS -5.2 ALOGPS
        pKa (strongest acidic) 10.36 ChemAxon
        pKa (strongest basic) -1 ChemAxon
        physiological charge 0 ChemAxon
        hydrogen acceptor count 10 ChemAxon
        hydrogen donor count 4 ChemAxon
        polar surface area 221.29 ChemAxon
        rotatable bond count 14 ChemAxon
        refractivity 218.29 ChemAxon
        polarizability 87.17 ChemAxon
        药物相互作用
        Drug Interaction
        Aprepitant Aprepitant may change levels of the chemotherapy agent, paclitaxel.
        Axitinib Avoid combination due to potential for decrease in serum concentration of axitinib.
        Carboplatin Platinum derivatives such as carboplatin may enhance the myelosuppressive effect of taxane derivatives such as paclitaxel. Administer taxane derivative before platinum derivative when given as sequential infusions to limit toxicity. Administering the taxane derivative before the platinum derivative seems prudent.
        Cisplatin Cisplatin increases the effect and toxicity of paclitaxel
        Clozapine Avoid combination due to the potential enhancement of agranulocytosis by clozapine.
        Conivaptan Avoid combination because it will likely increase the serum concentration of CYP3A4 substrates.
        Etravirine Paclitaxel, when used concomitantly with NNRTIs, may experience an increase in serum concentration. It is recommended to monitor for paclitaxel toxicity.
        Gemcitabine Paclitaxel increases the effect/toxicity of gemcitabine
        Natalizumab Avoid combination due to the increased risk of infection.
        Pazopanib Pazopanib increases exposure of paclitaxel
        Pimecrolimus Avoid combination due to the enhancement of adverse effects of immunosuppressants.
        Quinupristin This combination presents an increased risk of toxicity
        St. John's Wort Avoid combination due to potential decrease in serum concentration of paclitaxel.
        Tacrolimus Avoid combination of topical tacrolimus due to the potential enhancement of adverse effects of immunosuppressants.
        Telithromycin Telithromycin may reduce clearance of Paclitaxel. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Paclitaxel if Telithromycin is initiated, discontinued or dose changed.
        Tolbutamide Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Paclitaxel. Consider alternate therapy or monitor for changes in Paclitaxel therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.
        Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Concomitant therapy may also increase Trastuzumab serum concentration and decrease Paclitaxel serum concentrations. Monitor closely for adverse events and therapeutic response.
        Valrubicin The taxane derivative, Paclitaxel, may increase Valrubicin toxicity. Consider alternate therapy or monitor for toxic effects.
        Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of paclitaxel by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of paclitaxel if voriconazole is initiated, discontinued or dose changed.
        食物相互作用
        • Avoid echinacea.
        • Avoid grapefruit and grapefruit juice due to potential increase of paclitaxel.

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