Ifosfamide

Các tên gọi khác (7 ) :

3-(2-Chloroethyl)-2-((2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide
Ifosfamida
Ifosfamidum
Iphosphamide
Isofosfamide
Isophosphamide
Isosfamide

Thuốc chống ung thư và tác động vào hệ thống miễn dịch

Thuốc Gốc

Small Molecule

CAS: 3778-73-2

ATC: L01AA06

ĐG : APP Pharmaceuticals , http://www.apppharma.com

CTHH: C₇H₁₅Cl₂N₂O₂P

PTK: 261.086

Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. It is active as an alkylating agent and an immunosuppresive agent.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₇H₁₅Cl₂N₂O₂P

Phân tử khối

261.086

Monoisotopic mass

260.02481966

InChI

InChI=1S/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12)

InChI Key

InChIKey=HOMGKSMUEGBAAB-UHFFFAOYSA-N

IUPAC Name

3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2$l^{5}-oxazaphosphinan-2-one

Traditional IUPAC Name

ifosfamide

SMILES

ClCCNP1(=O)OCCCN1CCCl

Độ tan chảy

39-41 °C

Độ hòa tan

3780 mg/L

logP

0.86

logS

-1.2

pKa (strongest acidic)

13.24

pKa (Strongest Basic)

0.12

PSA

41.57 Å²

Refractivity

58.48 m³·mol^-1

Polarizability

23.94 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 : Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation. It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA. Ifosfamide is cycle-phase nonspecific.

Cơ Chế Tác Dụng : Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. It is active as an alkylating agent and an immunosuppresive agent. The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death.

Dược Động Học :

▧ Volume of Distribution :
Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. When given to pediatric patients, the volume of distribution was 21±1.6 L/m^2.
▧ Protein binding :
Ifosfamide shows little plasma protein binding.
▧ Metabolism :
Primarily hepatic. Ifosfamide is metabolized through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.
▧ Route of Elimination :
Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.
▧ Half Life :
7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.
▧ Clearance :
* 2.4±0.33 L/h/m^2 [pediatric patients]

Độc Tính : LD₅₀ (mouse) = 390-1005 mg/kg, LD₅₀ (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).

Chỉ Định : Used as a component of various chemotherapeutic regimens as third-line therapy for recurrent or refractory germ cell testicular cancer. Also used as a component of various chemotherapeutic regimens for the treatment of cervical cancer, as well as in conjunction with surgery and/or radiation therapy in the treatment of various soft tissue sarcomas. Other indications include treatment of osteosarcoma, bladder cancer, ovarian cancer. small cell lung cancer, and non-Hodgkin's lymphoma.

Tương Tác Thuốc :

Aprepitant Aprepitant may change levels of the chemotherapy agent, ifosfamide.
Bendamustine Increases toxicity through pharmacodynamic synergism. Additive myelosuppression.
Etravirine Ifosfamide, when administered concomitantly with etravirine (a strong CYP3A4 inducer), may experience an increase in the serum concentrations of its active metabolites. It is recommended to monitor for toxicity of ifosfamide therapy.
Pazopanib Ifosfamide decreases plasma levels of pazopanib.
Telithromycin Telithromycin may reduce clearance of Ifosfamide. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Ifosfamide if Telithromycin is initiated, discontinued or dose changed.
Ticlopidine Ticlopidine may decrease the metabolism and clearance of Ifosfamide. Consider alternate therapy or monitor for adverse/toxic effects of Ifosfamide if Ticlopidine is initiated, discontinued or dose changed.
Tranylcypromine Tranylcypromine, a strong CYP2A6 inhibitor, may decrease the metabolism and clearance of Ifosmadine.
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 ifosfamide by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of ifosfamide if voriconazole is initiated, discontinued or dose changed.

Liều Lượng & Cách Dùng : Injection, powder, for solution - Intravenous - 1 g, 3 g
Kit - Intravenous - 1-1 GM
Solution - Intravenous - 1 g/20 mL; 3 g/60 mL

Dữ Kiện Thương Mại

Giá thị trường

Biệt dược thương mại : Ifosfamide 1 gm vial

Giá bán buôn : USD >56.4

Đơn vị tính : vial
Biệt dược thương mại : Ifosfamide 3 gm vial

Giá bán buôn : USD >114.0

Đơn vị tính : vial
Biệt dược thương mại : Ifex 1 gm vial

Giá bán buôn : USD >163.04

Đơn vị tính : vial
Biệt dược thương mại : Ifex 3 gm vial

Giá bán buôn : USD >489.13

Đơn vị tính : vial
Biệt dược thương mại : Ifosfamide-mesna kit

Giá bán buôn : USD >787.5

Đơn vị tính : kit
Biệt dược thương mại : Ifex-mesnex kit

Giá bán buôn : USD >2709.98

Đơn vị tính : kit

Nhà Sản Xuất

Công ty : Celon

Sản phẩm biệt dược : Celofos
Công ty : Teva

Sản phẩm biệt dược : Cuantil
Công ty : Baxter

Sản phẩm biệt dược : Holoxan
Công ty : Baxter

Sản phẩm biệt dược : Ifex
Công ty : Baxter

Sản phẩm biệt dược : Mitoxana

Đóng gói

Công ty : APP Pharmaceuticals

Website : http://www.apppharma.com
Công ty : Baxter International Inc.

Website : http://www.baxter.com
Công ty : Bristol-Myers Squibb Co.

Website : http://www.bms.com
Công ty : Teva Pharmaceutical Industries Ltd.

Website : http://www.tevapharm.com

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB01181

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=3690

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=46508335

KEGG Compound

http://www.genome.jp/dbget-bin/www_bget?cpd:C07047

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D00343

ChemSpider

http://www.chemspider.com/Chemical-Structure.3562.html

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0703-3427-11

PharmGKB

http://www.pharmgkb.org/drug/PA449964

Wikipedia

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

RxList

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

Drugs.com

http://www.drugs.com/cdi/ifosfamide-solution.html

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