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药品详细

Ifosfamide (异环磷酰胺 )

化学结构式图
中文名
异环磷酰胺
英文名
Ifosfamide
分子式
Not Available
化学名
3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-1,3,2$l^{5}-oxazaphosphinan-2-one
分子量
Average: 261.086
Monoisotopic: 260.024819660
CAS号
3778-73-2
ATC分类
L01A 烷化剂
药物类型
small molecule
阶段
商品名
Cyfos;Holoxan 1000;IFEX;Ifex/Mesnex Kit;Ifosfamide/Mesna Kit;Isoendoxan;Mitoxana;Naxamide;
同义名
Asta Z 4942;I-Phosphamide;Ifosfamid;Ifosfamide Sterile;Ifosphamide;Ifsofamide;Iphosphamid;Iphosphamide;Isofosfamide;Isophosphamide;
基本介绍

Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. [PubChem]

生产厂家
  • App pharmaceuticals llc
  • Baxter healthcare corp
  • Bedford laboratories div ben venue laboratories inc
  • Sagent strides llc
  • Teva parenteral medicines inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Furlanut M, Franceschi L: Pharmacology of ifosfamide. Oncology. 2003;65 Suppl 2:2-6. Pubmed
  2. Fleming RA: An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy. 1997 Sep-Oct;17(5 Pt 2):146S-154S. Pubmed
  3. Wagner T: Ifosfamide clinical pharmacokinetics. Clin Pharmacokinet. 1994 Jun;26(6):439-56. Pubmed
  4. Allen LM, Creaven PJ, Nelson RL: Studies on the human pharmacokinetics of isophosphamide (NSC-109724). Cancer Treat Rep. 1976 Apr;60(4):451-8. Pubmed
  5. Brade WP, Herdrich K, Varini M: Ifosfamide—pharmacology, safety and therapeutic potential. Cancer Treat Rev. 1985 Mar;12(1):1-47. Pubmed
  6. Zalupski M, Baker LH: Ifosfamide. J Natl Cancer Inst. 1988 Jun 15;80(8):556-66. Pubmed
  7. Willits I, Price L, Parry A, Tilby MJ, Ford D, Cholerton S, Pearson AD, Boddy AV: Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer. Br J Cancer. 2005 May 9;92(9):1626-35. Pubmed
  8. Lokiec F: Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention. Ann Oncol. 2006 May;17 Suppl 4:iv33-6. Pubmed
  9. Schoenike SE, Dana WJ: Ifosfamide and mesna. Clin Pharm. 1990 Mar;9(3):179-91. Pubmed
  10. Dechant KL, Brogden RN, Pilkington T, Faulds D: Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs. 1991 Sep;42(3):428-67. Pubmed
剂型
Form Route Strength
Powder, for solution Intravenous
规格
Unit description Cost Unit
Ifex-mesnex kit 2709.98 USD kit
Ifosfamide-mesna kit 787.5 USD kit
Ifex 3 gm vial 489.13 USD vial
Ifex 1 gm vial 163.04 USD vial
Ifosfamide 3 gm vial 114.0 USD vial
Ifosfamide 1 gm vial 56.4 USD vial
化合物类型
Type small molecule
Classes
  • Organophosphate Esters
Substructures
  • Organophosphate Esters
  • Phosphoric Acids and Derivatives
  • Alkyl Halides
  • Heterocyclic compounds
适应症
Cancer 癌症;
药理
Indication 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.
Pharmacodynamics 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.
Mechanism of action 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.
Absorption Not Available
Volume of distribution Not Available
Protein binding Minimal
Metabolism

Primarily hepatic

Enzyme Metabolite Reaction Km Vmax
Prostaglandin G/H synthase 1 4-Hydroxyifosfamide 4-hydroxylation
Cytochrome P450 3A5 3-Dechloroethylifosfamide
Cytochrome P450 3A5 2-Dechloroethylifosfamide
Cytochrome P450 3A5 Chloroacetaldehyde
Cytochrome P450 3A4 3-Dechloroethylifosfamide
Cytochrome P450 3A4 2-Dechloroethylifosfamide
Cytochrome P450 3A4 Chloroacetaldehyde
Cytochrome P450 3A4 4-hydroxyifosfamide 4-hydroxylation 800 139.5
Cytochrome P450 2B6 3-Dechloroethylifosfamide
Cytochrome P450 2B6 2-Dechloroethylifosfamide
Cytochrome P450 2B6 Chloroacetaldehyde
Cytochrome P450 2B6 4-hydroxyifosfamide 4-hydroxylation 0 0
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
Clearance Not Available
Toxicity 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).
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00448 Ifosfamide Pathway SMP00448
理化性质
Properties
State solid
Melting point 39-41 oC
Experimental Properties
Property Value Source
water solubility 3780 mg/L PhysProp
logP 0.8 PhysProp
Predicted Properties
Property Value Source
water solubility 1.50e+01 g/l ALOGPS
logP 0.57 ALOGPS
logP 0.10 ChemAxon Molconvert
logS -1.24 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 41.57 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 58.48 ChemAxon Molconvert
polarizability 23.94 ChemAxon Molconvert
药物相互作用
Drug Interaction
Aprepitant Aprepitant may change levels of the chemotherapy agent, ifosfamide.
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.
食物相互作用
Not Available

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