Topotecan

Các tên gọi khác (3) :

9-[(dimethylamino)Methyl]-10-hydroxy-(4S)-camptothecin
Topotecane
Topotecanum

topoisomerase i inhibitors

Thuốc Gốc

Small Molecule

CAS: 119413-54-6

ATC: L01XX17

ĐG : GlaxoSmithKline Inc. , http://www.gsk.com

CTHH: C₂₃H₂₃N₃O₅

PTK: 421.4458

An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerases, type I. [PubChem]

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₃H₂₃N₃O₅

Phân tử khối

421.4458

Monoisotopic mass

421.163770861

InChI

InChI=1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1

InChI Key

InChIKey=UCFGDBYHRUNTLO-QHCPKHFHSA-N

IUPAC Name

(19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaene-14,18-dione

Traditional IUPAC Name

topotecan

SMILES

CC[C@@]1(O)C(=O)OCC2=C1C=C1N(CC3=CC4=C(C=CC(O)=C4CN(C)C)N=C13)C2=O

Độ tan chảy

213-218 °C

Độ hòa tan

1 mg/ml

logP

0.8

logS

-2.7

pKa (strongest acidic)

pKa (Strongest Basic)

9.83

PSA

103.2 Å²

Refractivity

115.02 m³·mol^-1

Polarizability

44.86 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

Dược Lực Học : Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug.

Cơ Chế Tác Dụng : An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA topoisomerases, type I. [PubChem] Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.

Dược Động Học :

▧ Protein binding :
35%
▧ Metabolism :
Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active.
▧ Route of Elimination :
Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%.
▧ Half Life :
2-3 hours

Độc Tính : The primary anticipated complication of overdosage would consist of bone marrow suppression.

Chỉ Định : For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy.

Tương Tác Thuốc :

Amiodarone The p-glycoprotein inhibitor, Amiodarone, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Atorvastatin The p-glycoprotein inhibitor, Atorvastatin, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Carboplatin Administration of Topotecan after Carboplatin therapy may increase the risk of hematologic toxicity, such as neutropenia and/or thrombocytopenia. A dose adjustment may be required or the sequence of administration reversed.
Carvedilol The p-glycoprotein inhibitor, Carvedilol, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Cisplatin Administration of Topotecan after Cisplatin therapy may increase the risk of hematologic toxicity, such as neutropenia and/or thrombocytopenia. A dose adjustment may be required or the sequence of administration reversed.
Clarithromycin The p-glycoprotein inhibitor, Clarithromycin, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Cyclosporine The p-glycoprotein inhibitor, Cyclosporine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Darunavir The p-glycoprotein inhibitor, Darunavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Dipyridamole The p-glycoprotein inhibitor, Dipyridamole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Erythromycin The p-glycoprotein inhibitor, Erythromycin, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Filgrastim Filgrastim may increase the adverse effects of Topotecan. Increased risk of prolonged neutropenia. Filgrastim should be administered at least 24 hours following Topotecan therapy. Monitor for signs and symptoms of neutropenia.
Gefitinib 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.
Imatinib 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.
Itraconazole The p-glycoprotein inhibitor, Itraconazole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Ketoconazole The p-glycoprotein inhibitor, Ketoconazole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Lapatinib The p-glycoprotein inhibitor, Lapatinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Lopinavir The p-glycoprotein inhibitor, Lopinavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Mefloquine The p-glycoprotein inhibitor, Mefloquine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Natalizumab The immunosuppressant, Topotecan, may increase the adverse effects of Natalizumab. Increased risk of Progressive Multifocal Leukoencephalopathy (PML) and other infections. Concurrent therapy should be avoided.
Nelfinavir The p-glycoprotein inhibitor, Nelfinavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Nicardipine The p-glycoprotein inhibitor, Nicardipine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Nilotinib The p-glycoprotein inhibitor, Nilotinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Oxaliplatin Administration of Topotecan after Oxaliplatin therapy may increase the risk of hematologic toxicity, such as neutropenia and/or thrombocytopenia. A dose adjustment may be required or the sequence of administration reversed.
Pantoprazole The BCRP/ABCG2 inhibitor, Pantaprazole, may increase the bioavailability and serum concentration of oral Topotecan. Monitor for change in the therapeutic and adverse effects of Topotecan if Pantaprazole is initiated, discontinued or dose changed.
Progesterone The p-glycoprotein inhibitor, Progesterone, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Propranolol The p-glycoprotein inhibitor, Propranolol, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Quinidine The p-glycoprotein inhibitor, Quinidine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Ranolazine The p-glycoprotein inhibitor, Ranolazine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Reserpine The p-glycoprotein inhibitor, Reserpine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Ritonavir The p-glycoprotein inhibitor, Ritonavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Saquinavir The p-glycoprotein inhibitor, Saquinavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Sunitinib The p-glycoprotein inhibitor, Sunitinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Tacrolimus The p-glycoprotein inhibitor, Tacrolimus, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Tamoxifen The p-glycoprotein inhibitor, Tamoxifen, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Verapamil The p-glycoprotein inhibitor, Verapamil, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Liều Lượng & Cách Dùng : Powder, for solution - Intravenous

Dữ Kiện Thương Mại

Giá thị trường

Biệt dược thương mại : Hycamtin 0.25 mg capsule

Giá bán buôn : USD >89.73

Đơn vị tính : capsule
Biệt dược thương mại : Hycamtin 1 mg capsule

Giá bán buôn : USD >358.92

Đơn vị tính : capsule
Biệt dược thương mại : Hycamtin 4 mg vial

Giá bán buôn : USD >1306.1

Đơn vị tính : vial

Nhà Sản Xuất

Công ty :

Sản phẩm biệt dược : Hycamtin

Đóng gói

Công ty : GlaxoSmithKline Inc.

Website : http://www.gsk.com
Công ty : Pfizer Animal Health

Website : http://www.pfizerah.com

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB01030

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=60700

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46505204

KEGG Compound

http://www.genome.jp/dbget-bin/www_bget?cpd:C11158

ChemSpider

http://www.chemspider.com/Chemical-Structure.54705.html

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0007-4201-01

PharmGKB

http://www.pharmgkb.org/drug/PA451729

Wikipedia

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

RxList

http://www.rxlist.com/cgi/generic2/topotec.htm

Drugs.com

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

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