Gefitinib

Các tên gọi khác (5 ) :

4-(3'-chloro-4'-Fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline
Gefitinib
Iressa
N-(3-chloro-4-Fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamine
ZD 1839

Thuốc Gốc

Small Molecule

CAS: 184475-35-2

ATC: L01XE02

ĐG : AstraZeneca Inc. , http://www.astrazeneca.ca

CTHH: C₂₂H₂₄ClFN₄O₃

PTK: 446.902

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]

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₂H₂₄ClFN₄O₃

Phân tử khối

446.902

Monoisotopic mass

446.152096566

InChI

InChI=1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)

InChI Key

InChIKey=XGALLCVXEZPNRQ-UHFFFAOYSA-N

IUPAC Name

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

Traditional IUPAC Name

gefitinib

SMILES

COC1=C(OCCCN2CCOCC2)C=C2C(NC3=CC(Cl)=C(F)C=C3)=NC=NC2=C1

Độ hòa tan

Sparingly soluble (

logP

3.2

logS

-4.2

pKa (strongest acidic)

16.11

pKa (Strongest Basic)

6.85

PSA

68.74 Å²

Refractivity

117.51 m³·mol^-1

Polarizability

46.11 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

Rule of Five

true

Ghose Filter

true

MDDR-Like Rule

true

pKa

5.4 and 7.2

Dược Lực Học : 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.

Cơ Chế Tác Dụng : 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] 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.

Dược Động Học :

▧ Absorption :
Absorbed slowly after oral administration with a mean bioavailability of 60%. Peak plasma levels occurs 3-7 hours post-administration. Food does not affect the bioavailability of gefitinib.
▧ Volume of Distribution :
* 1400 L [IV administration]
▧ Protein binding :
90% primarily to serum albumin and alpha 1-acid glycoproteins (independent of drug concentrations).
▧ 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 [IV administration]
▧ Clearance :
* 595 mL/min [IV administration]

Độc Tính : 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.

Chỉ Định : 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.

Tương Tác Thuốc :

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
Dicoumarol 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.
Etravirine Gefitinib, when administered concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to increase gefitinib dosage, if clinically appropriate, and to monitor for gefitinib therapy for efficacy and toxicity.
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.
Rifampicin 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.

Liều Lượng & Cách Dùng : Tablet - Oral - 250 mg

Dữ Kiện Thương Mại

Giá thị trường

Biệt dược thương mại : Tarceva 25 mg tablet

Giá bán buôn : USD >52.78

Đơn vị tính : tablet
Biệt dược thương mại : Iressa 250 mg tablet

Giá bán buôn : USD >68.08

Đơn vị tính : tablet
Biệt dược thương mại : Tarceva 100 mg tablet

Giá bán buôn : USD >144.98

Đơn vị tính : tablet
Biệt dược thương mại : Tarceva 150 mg tablet

Giá bán buôn : USD >163.98

Đơn vị tính : tablet

Nhà Sản Xuất

Công ty : AstraZeneca

Sản phẩm biệt dược : Iressa

Đóng gói

Công ty : AstraZeneca Inc.

Website : http://www.astrazeneca.ca
Công ty : Genentech Inc.

Website : http://www.gene.com

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB00317

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=123631

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46508649

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D01977

ChemSpider

http://www.chemspider.com/Chemical-Structure.110217.html

BindingDB

http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=5447

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0310-0482-30

PharmGKB

http://www.pharmgkb.org/drug/PA131301952

Wikipedia

http://en.wikipedia.org/wiki/Gefitinib

RxList

http://www.rxlist.com/cgi/generic3/iressa.htm

Drugs.com

http://www.drugs.com/cdi/gefitinib.html

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