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异环磷酰胺代谢物
异环磷酰胺是氮芥类抗肿瘤药物之一，其代谢产物包括酮(异)环磷酰胺和羧基(异)磷酰胺。
这些代谢物是由可溶性酶如醛脱氢酶分别氧化生成的，无细胞毒作用，是从尿中排泄的失活产物。
未经氧化的醛(异)磷酰胺可在细胞内外部分进行自发降解，生成活性代谢产物(异)磷酰胺氮芥(PM)和丙烯醛。
其中，(异)磷酰胺氮芥(PM)是主要的代谢产物，其在尿中的排泄极少，与后两种相比几乎可以忽略，因此几乎所有被活化的CPIFO都以代谢物的形式排出体外。
此外，3’5’核酸内切酶可加速活化过程。
前两种代谢物在尿中的排泄极少，与后两种相比几乎可以忽略，因此几乎所有被活化的CPIFO都以代谢物的形式排出体外。
以上内容仅供参考，建议查阅专业书籍或咨询专业人士获取更准确的信息。
药物名称异环磷酰胺
药物别名和乐⽣，HOLOXAN，IFO
英⽂名称 Ifosfamide
说 明注射⽤异环磷酸胺：每瓶0.5g；1.0g；2.0g。
功⽤作⽤⾻及软组织⾁瘤、⾮⼩细胞肺癌、乳腺癌、头颈部癌、⼦宫颈癌、⾷管癌。
⽤法⽤量常⽤剂量为2.5～5.0g／m2，每⽇1次，静脉滴注，连续5天，每3～4周重复1次。
剂量为18g／m2静脉滴注，连续4天。
注意事项限制剂量提⾼的主要毒性为泌尿道刺激，如不给尿路保护剂有18％～40％可出现⾎尿。
所以⼀般必须配合应⽤尿路保护剂美司纳及适当⽔化。
肾毒性表现为⾎肌酐升⾼，⾼剂量时甚⾄可导致肾⼩管坏死。
⼉童长期应⽤异环磷酰胺可引起Fanconi综合征。
所以肾功能不全的病⼈应慎⽤。
剂量过⾼、肾功能不全和既往⽤过顺铂的病⼈可有神经毒性，常表现为昏睡、意识不清，常在药物治疗期内或停药后短期内出现。
⼀般认为是异环磷酰胺去氯⼄基后形成的氯⼄醛引起。
⾻髓抑制也是剂量限制性毒性，⽩细胞和⾎⼩板下降常出现于给药后第8～12天。
其他也可有恶⼼呕吐、脱发等。
个别报告在⾼剂量可有肺炎和⼼脏毒性。
IfosfamideBarbara J.Rider Tulane Health Sciences Center,New Orleans,USAã2007Elsevier Inc.All rights reserved.IntroductionIfosfamide,an analog of cyclophosphamide,is an alkylating agent that is effective against a variety of tumors.Its major advantage over cyclophosphamide is that ifosfamide is less myelotoxic Chabner et al(2001).NomenclatureName of the ClinicalFormIfosfamideRelated Names Source:EMTREE Ifosfamide;asta24942;asta4942;asta z4942;3(2 chloroethyl)2(2chloroethylamino)1,3,2 oxazaphosphorinane2oxide;3(2chloroethyl)2(2chloroethylamino)tetrahydro2h1,3,2oxazaphosphorine 2oxide;cyfos;holoxan;ifex;ifomide;ifosfamid; iphosphamide;isocyclophosphamide;isoendoxan; isofosfamide;isophosphamide;mitoxana;mjf9325; naxamide;n,3bis(2chloroethyl)tetrahydro2h1,3,2 oxazaphosphorin2amino2oxide;nsc109724;z4942; Ifosamide;3(2chloroethyl)2(2chloroethylamino)1,3,2 oxazaphosphorinane2oxide;3(2chloroethyl)2(2 chloroethylamino)tetrahydro2h1,3,2oxazaphosphorine2oxide;asta24942;asta z4942;asta24942;asta4942;mjf9325;n,3bis(2chloroethyl)tetrahydro2h1,3,2 oxazaphosphorin2amino2oxide;nsc109724;z4942Chemical Names N,3-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine2-oxideCAS Number3778-73-2Basic ChemistryChemical StructureStructureComments Related structurally to cyclophosphamide.1ChemicalFormulaC7H15Cl2N2O2P PropertiesPhysicalProperties Ifosfamide is an off-white lyophilized powder with a melting point of between39–41 C.While it can be stored at room temperature or under refrigeration,it should be protected from temperatures above 35 C at which it will liquefy and decompose Dorr and Fritz(1980), Budavari(1996).MolecularWeight261.087Solubility Ifosfamide is soluble in water.The intact vial is stable for up to5years.The reconstituted solution is stable for1week at room temperatureand for6weeks under refrigeration Dorr and Fritz(1980).Human PharmacokineticsThe pharmacokinetics of ifosfamide are dose-dependent.At high single doses of3.8–5.0 g/m2,plasma decay is biphasic with a terminal half-life of approximately15hours. Urinary recovery is from70–86%of the administered dose,with about62%being excreted as parent compound.Lower fractionated doses of ifosfamide(1.6–2.4g/m2/ day)exhibit a monoexponential plasma decay with a terminal half-life of about7hours. Urinary excretion of unchanged drug is only12–18%of the dose after72hours.The renal clearance of ifosfamide is21.3ml/min with a single bolus dose,and18.7ml/min with fractionated doses Sifton(2002),Dorr and Fritz(1980).Pharmacokinetic PropertiesValueUnits Prep.andRoute ofAdmin.Reference CommentsAbsorptionBioavailability92% 1.5g/m2,p.o.Chabner et al(2001) DistributionVolume of Distribution 12.5l/m2 5.0g/m2,i.v.Chabner et al(2001)Plasma ProteinBindingNegligibleMetabolism Metabolized by CYP450s to active compound.Plasma Half-Life7.0hrs i.v.Sifton(2002)The plasma half-life isdose-dependent.Thevalue shown is for lowfractionated doses. Bio Half-LifeClearance63ml/min/m21.5g/m2,i.v.Chabner et al(2001)The clearance ofifosfamide is dose-dependent.Routes of Elimination Ifosfamide and its metabolites are excreted primarily in urine.Ifosfamide 2Targets-PharmacodynamicsTo be active,ifosfamide requires metabolic conversion by cytochrome P450enzymes in the liver.Similar to cyclophosphamide,ifosfamide is activated to4-hydroxyifosfamide, which degrades to4-ketoifosfamide,which,in turn,is converted to ifosphoramide,the active metabolite,and acrolein,which is most likely responsible for hemorrhagic cystitis. The active metabolite induces crosslinking of DNA,thereby inhibiting DNA replication Chabner et al(2001).Target Name(s):DNATherapeuticsIfosfamide is a broad-spectrum antineoplastic agent shown to be effective against a variety of cancers,including leukemias,solid tumors and lymphomas.It is typically employed in combination with other antineoplastic agents,but may be used alone for the treatment of Burkitt’s Lymphoma.IndicationsValue Units Prep.and Routeof Admin.Reference CommentsCancerDosage 1.2gm/m2/day i.v.for5consecutivedays Sifton(2002)Repeat treatmentevery3weeks.ContraindicationsIfosfamide is contraindicated in those known to be hypersensitive to it and in those with depressed bone marrow function.Adverse EffectsAdverse effects associated with the use of ifosfamide include hemorrhagic cystitis,nausea, vomiting,alopecia,and myelosuppression.Agent-Agent InteractionsAgent Name Mode of InteractionBarbiturates Co-administration of barbiturates enhances the metabolic activation of ifosfamide.Ifosfamide3Pre-Clinical ResearchPharmacokinetics PotencyValue UnitsOrgan/Tissue Prep.and Route of Admin.Cell Line/Type Effects Exp.End Point Reference CommentsRatLD50150–160mg/kgi.p.Budavari(1996)Book CitationsDorr,R.T,Fritz,W.L.,1980.Ifosfamide.Cancer Chemotherapy Handbook ,pp.472–479,Elsevier,New York,NY.Sifton,D.W.,2002.Ifex.Sifton,D.W.(Ed.),Physicians’Desk Reference ,Edition 56,pp.1123–1124,Medical Economics Company,Montvale,New Jersey..Budavari,S.,1996.Ifosfamide.Budavari,S.(Ed.),The Merck Index ,Edition 12,pp.841–842,Merck and Co.,Inc.,Rahway,NJ.Chabner,B.A.,Ryan,D.P.,Paz-Ares,L.,Garcia-Carbonero,R.,Calabresi,P.,2001.Antineoplastic Agents.Hardman,J.G.,Limbird,L.E.(Ed.),Goodman and Gilman’s The Pharmacological Basis of Therapeutics ,Edition 10,pp.1389–1459,McGraw-Hill,New York,NY.Ifosfamide4。
