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药品详细

Imatinib (伊马替尼 )

化学结构式图
中文名
伊马替尼
英文名
Imatinib
分子式
Not Available
化学名
N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamide
分子量
Average: 493.6027
Monoisotopic: 493.259008649
CAS号
152459-95-5
ATC分类
L01X 其它抗肿瘤药
药物类型
small molecule
阶段
商品名
Gleevec;Glivec;
同义名
Imatinib Mesylate;Imatinib Methansulfonate;
基本介绍

Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). It is occasionally referred to as CGP57148B or STI571 (especially in older publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies.

It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells.

生产厂家
  • Novartis pharmaceuticals corp
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Deininger MW, Druker BJ: Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol Rev. 2003 Sep;55(3):401-23. Epub 2003 Jul 17. Pubmed
  2. Vigneri P, Wang JY: Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001 Feb;7(2):228-34. Pubmed
  3. Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL: Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51. Pubmed
  4. Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, Cooper ME: Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol. 2004 May;24(5):935-42. Epub 2004 Feb 26. Pubmed
  5. Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D: Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med. 2005 Jul;11(7):731-9. Epub 2005 Jun 26. Pubmed
剂型
Form Route Strength
Capsule Oral
Tablet Oral
规格
Unit description Cost Unit
Gleevec 400 mg tablet 174.38 USD tablet
Gleevec 100 mg tablet 41.69 USD tablet
化合物类型
Type small molecule
Classes
  • Benzoyl Derivatives
  • Benzamides
Substructures
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Pyridines and Derivatives
  • Piperazines
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Pyrimidines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Imines
  • Benzoyl Derivatives
  • Cyanamides
  • Benzamides
  • Anilines
适应症
Cancer 癌症;
药理
Indication For the treatment Philadelphia chromosome positive chronic myeloid leukemia (CML) and malignant gastrointestinal stromal tumors (GIST).
Pharmacodynamics Imatinib is an antineoplastic agent used to treat chronic myelogenous leukemia. Imatinib is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of Abl with Bcr (breakpoint cluster region), termed Bcr-Abl. As this is now a continuously active tyrosine kinase, Imatinib is used to decrease Bcr-Abl activity.
Mechanism of action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib also inhibits the receptor tyrosine kinases for platelet derived growth factor (PDGF) and stem cell factor (SCF) - called c-kit. Imatinib was identified in the late 1990s by Dr Brian J. Druker. Its development is an excellent example of rational drug design. Soon after identification of the bcr-abl target, the search for an inhibitor began. Chemists used a high-throughput screen of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.
Absorption Imatinib is well absorbed with mean absolute bioavailability is 98% with maximum levels achieved within 2-4 hours of dosing
Volume of distribution Not Available
Protein binding Very high (95%)
Metabolism

Primarily hepatic via CYP3A4. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4.

Enzyme Metabolite Reaction Km Vmax
Prostaglandin G/H synthase 1 AFN911 benzyl hydroxylation
Prostaglandin G/H synthase 1 CGP71422 N-4 oxidation
Prostaglandin G/H synthase 1 CGP72383 N-oxidation
Cytochrome P450 3A5 CGP74588 N-demethylation
Cytochrome P450 2D6 CGP74588 N-demethylation
Cytochrome P450 1A2 CGP74588 N-demethylation
Cytochrome P450 3A4 CGP74588 N-demethylation
Cytochrome P450 3A4 N-desmethylimatinib (CGP 74588) 0 0
Cytochrome P450 2C9 CGP74588 N-demethylation
Route of elimination Imatinib elimination is predominately in the feces, mostly as metabolites.
Half life 18 hours for Imatinib, 40 hours for its major active metabolite, the N-desmethyl derivative
Clearance
  • 8 L/h [50-year-old CML and GIST patient weighing 50 kg]
  • 14 L/h [50-year-old CML and GIST patient weighing 100 kg]
Toxicity Side effects include nausea, vomiting, diarrhea, loss of appetite, dry skin, hair loss, swelling (especially in the legs or around the eyes) and muscle cramps
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Melting point 226 oC (mesylate salt)
Experimental Properties
Property Value Source
water solubility Very soluble in water at pH < 5.5 (mesylate salt) PhysProp
logP 3 PhysProp
Predicted Properties
Property Value Source
water solubility 1.46e-02 g/l ALOGPS
logP 3.47 ALOGPS
logP 4.38 ChemAxon Molconvert
logS -4.53 ALOGPS
pKa 13.45 ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 86.28 ChemAxon Molconvert
rotatable bond count 7 ChemAxon Molconvert
refractivity 148.93 ChemAxon Molconvert
polarizability 55.54 ChemAxon Molconvert
药物相互作用
Drug Interaction
Acenocoumarol Imatinib may increase the anticoagulant effect of acenocoumarol.
Acetaminophen Increased hepatic toxicity of both agents
Anisindione Imatinib may increase the anticoagulant effect of anisindione.
Aprepitant Aprepitant may change levels of the chemotherapy agent, imatinib.
Atorvastatin Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if imatinib is initiated, discontinued or dose changed.
Bromazepam Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if imatinib is initiated, discontinued or dose changed. Dosage adjustments may be required.
Carbamazepine Carbamazepine, a strong CYP3A4 inducer, may increase the metabolism of imatinib. Imatinib, a strong CYP3A4 inhibitor, may increase the metabolism of carbamazepine. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or dose changed.
Cerivastatin Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of cerivastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cerivastatin if imatinib is initiated, discontinued or dose changed.
Clarithromycin The macrolide, clarithromycin, may increase the serum concentration of imatinib.
Cyclosporine Imatinib increases the effect and toxicity of cyclosporine
Dantrolene Imatinib may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if imatinib is initiated, discontinued or dose changed.
Dexamethasone Dexamethasone may decrease levels of imatinib.
Dicumarol Imatinib may increase the anticoagulant effect of dicumarol.
Erythromycin The macrolide, erythromycin, may increase the serum concentration of imatinib.
Ethotoin The hydantoin decreases the levels of imatinib
Fosphenytoin The hydantoin decreases the levels of imatinib
Itraconazole Itraconazole may increase the levels of imatinib.
Josamycin The macrolide, josamycin, may increase the serum concentration of imatinib.
Ketoconazole Ketoconazole may increase the levels of imatinib.
Lovastatin Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of lovastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of lovastatin if imatinib is initiated, discontinued or dose changed.
Mephenytoin The hydantoin decreases the levels of imatinib
Nifedipine Imatinib increases the effect and toxicity of nifedipine
Phenobarbital Phenobarbital decreases levels of imatinib
Phenytoin The hydantoin decreases the levels of imatinib
Pimozide Imatinib may increase the effect and toxicity of pimozide.
Rifampin Rifampin decreases levels of imatinib
Simvastatin Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of simvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of simvastatin if imatinib is initiated, discontinued or dose changed.
St. John's Wort St. John's Wort decreases levels of imatinib
Tacrolimus The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Imatinib is initiated, discontinued or dose changed.
Tadalafil Imatinib may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.
Tamoxifen Imatinib may increase the serum concentration of Tamoxifen by decreasing its metabolism and clearance. Imatinib may also decrease the therapeutic effect of Tamoxifen by decreasing active metabolite production. Monitor for changes in the therapeutic/adverse effects of Tamoxifen if Imatinib is initiated, discontinued or dose changed.
Tamsulosin Imatinib, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Imatinib is initiated, discontinued, or dose changed.
Telithromycin Co-administration may result in altered plasma concentrations of Imatinib and/or Telithromycin. Consider alternate therapy or monitor the therapeutic/adverse effects of both agents.
Temsirolimus Imatinib may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.
Teniposide The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Imatinib is initiated, discontinued or dose changed.
Tiagabine The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Imatinib is initiated, discontinued or dose changed.
Tolterodine Imatinib may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.
Topotecan The BCRP/ABCG2 inhibitor, Imatinib, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Imatinib is initiated, discontinued or dose changed.
Tramadol Imatinib may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Imatinib may decrease the effect of Tramadol by decreasing active metabolite production.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Trazodone The CYP3A4 inhibitor, Imatinib, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Imatinib is initiated, discontinued or dose changed.
Trimipramine The strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Imatinib is initiated, discontinued or dose changed.
Vardenafil Imatinib, a strong CYP3A4 inhibitor, may reduce the metabolism and clearance of Vardenafil. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Vardenafil.
Venlafaxine Imatinib, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Imatinib is initiated, discontinued, or dose changed.
Verapamil Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Imatinib is initiated, discontinued or dose changed.
Vinblastine Imatinib, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Imatinib is initiated, discontinued or dose changed.
Vincristine Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Imatinib is initiated, discontinued or dose changed.
Vinorelbine Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Imatinib is initiated, discontinued or dose changed.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of imatinib by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of imatinib if voriconazole is initiated, discontinued or dose changed.
Warfarin Imatinib may increase the anticoagulant effect of warfarin increasing the risk of bleeding. Monitor for changes in prothrombin time and therapeutic and adverse effects of warfarin if imatinib is initiated, discontinued or dose changed.
Zonisamide Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if imatinib is initiated, discontinued or dose changed.
Zopiclone Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if imatinib is initiated, discontinued or dose changed.
食物相互作用
  • Take with food to reduce the incidence of gastric irritation. Follow with a large glass of water. A lipid rich meal will slightly reduce and delay absorption. Avoid grapefruit and grapefruit juice throughout treatment, grapefruit can significantly increase serum levels of this product.

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