药品详细

Gefitinib (吉非替尼 )

基本信息
剂型规格
适应症
药理
临床
理化性质
相互作用
文档
专利
Pathway
文献
序列

化学结构式图

中文名

吉非替尼

英文名

Gefitinib

分子式

Not Available

化学名

N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine

分子量

Average: 446.902
Monoisotopic: 446.152096566

CAS号

184475-35-2

ATC分类

L01X 其它抗肿瘤药

药物类型

small molecule

阶段

商品名

Iressa;Irressat;Tarceva;

同义名

ZD-1839;ZD1839;

基本介绍

Gefitinib (originally coded ZD1839) is a drug used in the treatment of certain types of cancer. Acting in a similar manner to erlotinib (marketed as Tarceva), gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa. [Wikipedia]

生产厂家

Astrazeneca uk ltd

封装厂家

参考

Synthesis Reference

Not Available

General Reference

Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H: EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. Epub 2004 Aug 25. Pubmed
Sordella R, Bell DW, Haber DA, Settleman J: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004 Aug 20;305(5687):1163-7. Epub 2004 Jul 29. Pubmed

剂型

Form	Route	Strength
Tablet	Oral

规格

Unit description	Cost	Unit
Tarceva 150 mg tablet	163.98 USD	tablet
Tarceva 100 mg tablet	144.98 USD	tablet
Iressa 250 mg tablet	68.08 USD	tablet
Tarceva 25 mg tablet	52.78 USD	tablet

化合物类型

Type	small molecule

Classes

Quinazolines

Substructures

Quinazolines
Aliphatic and Aryl Amines
Phenols and Derivatives
Ethers
Benzene and Derivatives
Aryl Halides
Halobenzenes
Pyrimidines and Derivatives
Catechols
Heterocyclic compounds
Aromatic compounds
Anisoles
Morpholines
Cyanamides
Phenyl Esters
Anilines

适应症

Cancer 癌症;

药理

Indication

For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.

Pharmacodynamics

Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.

Mechanism of action

Gefitinib inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited; and malignant cells are inhibited. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. Overexpression leads to inappropriate activation of the apoptotic Ras signal transduction cascade, eventually leading to uncontrolled cell proliferation.

Absorption

Absorbed slowly after oral administration with mean bioavailability of 60%.

Volume of distribution

1400 L

Protein binding

90% primarily to serum albumin and alpha 1-acid glycoproteins.

Metabolism

Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.

Route of elimination

Elimination is by metabolism (primarily CYP3A4) and excretion in feces. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.

Half life

48 hours

Clearance

595 mL/min

Toxicity

The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m² (about 80 times the recommended clinical dose on a mg/m² basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash.

Affected organisms

Humans and other mammals

Pathways

Pathway	Name	SMPDB ID
	Gefitinib Pathway	SMP00473

理化性质

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
water solubility	Sparingly soluble (	PhysProp
logP	3.2	PhysProp

Predicted Properties

Property	Value	Source
water solubility	2.70e-02 g/l	ALOGPS
logP	4.02	ALOGPS
logP	3.75	ChemAxon Molconvert
logS	-4.22	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	7	ChemAxon Molconvert
hydrogen donor count	1	ChemAxon Molconvert
polar surface area	68.74	ChemAxon Molconvert
rotatable bond count	8	ChemAxon Molconvert
refractivity	117.51	ChemAxon Molconvert
polarizability	46.11	ChemAxon Molconvert

药物相互作用

Drug	Interaction
Acenocoumarol	Gefitinib may increase the anticoagulant effect of acenocoumarol.
Amobarbital	The CYP3A4 inducer, amobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Anisindione	Gefitinib may increase the anticoagulant effect of anisindione.
Aprobarbital	The CYP3A4 inducer, aprobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Butabarbital	The CYP3A4 inducer, butabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Butalbital	The CYP3A4 inducer, butalbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Butethal	The CYP3A4 inducer, butethal, may decrease the serum concentration and therapeutic effects of gefitinib.
Carbamazepine	The CYP3A4 inducer, carbamazepine, may decrease the serum concentration and therapeutic effects of gefitinib.
Clarithromycin	This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Dicumarol	Gefitinib may increase the anticoagulant effect of dicumarol.
Dihydroquinidine barbiturate	The CYP3A4 inducer, dihydroquinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.
Erythromycin	This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Ethotoin	The CYP3A4 inducer, ethotoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Fosphenytoin	The CYP3A4 inducer, fosphenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Heptabarbital	The CYP3A4 inducer, heptabarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Hexobarbital	The CYP3A4 inducer, hexobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Itraconazole	Itraconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of gefitinib. Monitor for changes in the therapeutic and adverse effects of gefitinib if itraconazole is initiated, discontinued or dose changed.
Ketoconazole	This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Mephenytoin	The CYP3A4 inducer, mephenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Methohexital	The CYP3A4 inducer, methohexital, may decrease the serum concentration and therapeutic effects of gefitinib.
Methylphenobarbital	The CYP3A4 inducer, methylphenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Pentobarbital	The CYP3A4 inducer, pentobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Phenobarbital	The CYP3A4 inducer, phenobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
Phenytoin	The CYP3A4 inducer, phenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.
Primidone	The CYP3A4 inducer, primidone, may decrease the serum concentration and therapeutic effects of gefitinib.
Quinidine barbiturate	The CYP3A4 inducer, quinidine barbiturate, may decrease the serum concentration and therapeutic effects of gefitinib.
Rifampin	Rifampin reduces levels and efficacy of gefitinib
Ritonavir	This CYP3A4 inhibitor increases levels/toxicity of gefitinib
Secobarbital	The CYP3A4 inducer, secobarbital, may decrease the serum concentration and therapeutic effects of gefitinib.
St. John's Wort	The CYP3A4 inducer, St. John's Wort, may decrease the serum concentration and therapeutic effects of gefitinib.
Talbutal	The CYP3A4 inducer, talbutal, may decrease the serum concentration and therapeutic effects of gefitinib.
Telithromycin	Telithromycin may reduce clearance of Gefitinib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Gefitinib if Telithromycin is initiated, discontinued or dose changed.
Topotecan	The BCRP/ABCG2 inhibitor, Gefitnib, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Gefitinib is initiated, discontinued or dose changed.
Trastuzumab	Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Voriconazole	Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of gefitinib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of gefitinib if voriconazole is initiated, discontinued or dose changed.
Warfarin	Gefitinib may increase the anticoagulant effect of warfarin.

食物相互作用

Avoid fresh grapefruit and its juice during therapy as grapefruit may increase serum product levels.
Take without regard to meals.

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