Chemical Properties
Crystalline Solid
Originator
Holoxan,Lucien,France,1976
Definition
ChEBI: The simplest member of the class of ifosfamides that is 1,3,2-oxazaphosphinan-2-amine 2-oxide substituted by 2-chloroethyl groups on both the nitrogen atoms respectively. It is a nitrogen mustard alkylating agent used in the treatment of advanced breast c
ncer.
Indications
Ifosfamide (Ifex) is an analogue of cyclophosphamide
that requires metabolic activation to form 4-hydroxyifosfamide.
In general, the metabolism, serum half-life,
and excretion of ifosfamide are similar to those of cyclophosphamide.
Ifosfamide is active against a broad spectrum of tumors,
including germ cell cancers of the testis, lymphomas,
sarcomas, and carcinomas of the lung, breast,
and ovary. It is thought to be more active than cyclophosphamide
in germ cell cancers and sarcomas.
Ifosfamide is less myelosuppressive than cyclophosphamide
but is more toxic to the bladder. It also may
produce alopecia, nausea, vomiting, infertility, and second
tumors, particularly acute leukemias. Neurological
symptoms including confusion, somnolence, and hallucinations
have also been reported. It is recommended
that ifosfamide be coadministered with the thiol compound
mesna (Mesnex) to avoid hemorrhagic cystitis.
Manufacturing Process
127.6 g (1.1 mols) of N-(2-chloroethyl)-amine hydrochloride are suspended in
a solution of 218 g (1 mol) of N-(2-chloroethyl)-N,O-propylene phosphoric
acid ester amide monochloride in 600 cc of methylene dichloride, and 212 g of
triethylamine are added thereto dropwise with stirring. The reaction mixture is
heated to boiling by the reaction heat. After termination of the addition, the
reaction mixture is heated to boiling for another 2 hours. Thereafter, it is
cooled to room temperature and the precipitated triethylamine hydrochloride
is separated by filtration with suction. The filtrate is extracted with about 60cc
of dilute hydrochloric acid (pH 3), then twice with about 60 cc of water,
thereafter with about 60 cc of dilute soda lye and finally twice with about 60
cc of water. After drying over anhydrous sodium sulfate, methylene dichloride
is distilled off under normal pressure. The oily residue is dried in a vacuum
and thereafter extracted in a perforator with 500 cc of anhydrous ether. The
oily extract crystallizes upon inoculation and standing in an ice box. After
standing for several hours, the precipitate is filtered off, washed with a small
amount of cold ether and dried in a vacuum at room temperature. Yield: 185
g (71% of the theoretical). This material is also identified as 3-(2-
chloroethyl)-2-(2-chloroethylamino)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-
oxide; generic name: ifosfamide. F.P.: 39°C to 41°C.
Brand name
Ifex (Bristol-Myers Squibb).
Therapeutic Function
Antineoplastic
General Description
Ifosfamide is available in 1- and 3-g vials for IV administrationas Food and Drug Administration (FDA)-approvedthird-line therapy in the treatment of testicular cancer. It has also been utilized (although not FDA approved) in the treatmentof a wide variety of cancers including Hodgkin’s andnon-Hodgkin’s lymphoma, soft tissue sarcoma, germ celltumors, small cell lung cancer, non–small cell lung cancer(NSCLC), cancers of the head and neck, bladder cancer, cervicalcancer, and Ewing sarcoma. Coadministration ofmesna is recommended. The mechanisms of resistance areidentical to those seen with cyclophosphamide. The drug iswidely distributed with a low extent of protein binding(20%). Metabolism primarily by CYP3A4/5 and CYP2B6 isrequired for activation of the compound. Theagent is administered as the racemic mixture as a result ofthe presence of the chiral phosphorus atom, and differentialmetabolism of the R- and S-isomers has been observed. Incontrast to cyclophosphamide, there is a greater amount ofdeactivation of the agent by N-dechloroethylation and subsequentlymore chloroacetaldehyde is produced, which mayresult in a greater amount of neurotoxicity and nephrotoxicitythan seen with cyclophosphamide. The N-dechloroethylatedmetabolites are the predominate species seen in theplasma. The parent and metabolites are eliminated inthe urine with an elimination half-life of 3 to 10 hours. Themajor components found in the urine are the dechlorethylatedmetabolites. Dose-limiting toxicities include myelosuppressionand bladder toxicity. Other adverse effectsinclude nausea, alopecia, amenorrhea, inappropriate secretionof antidiuretic hormone, as well as the production ofsecondary cancers. Neurotoxicity, which is associated withthe production of chloroacetaldehyde presents as confusion,seizure, weakness, and hallucination, and coma may occur.
Biological Activity
Ifosfamide is a nitrogen mustard compound th at is a structural isomer of cyclophosphamide. Ifosfamide is a prodrug th at must be transformed by cytochrome P450 to the biologically active component. It is used as an antineoplastic agent in cancer chemotherapybut ifosfamide is more likely to cause renal toxicity than cyclophosphamide.
Clinical Use
Ifosamide currently is used as “third-line” therapy against testicular cancer, although it also has shown activity in a number of solid tumors and hematologic cancers.
Side effects
Patients on ifosfamide (but not cyclophosphamide) commonly exhibit central nervous system (CNS) toxicity. In severe forms, CNS depression can progress to coma and death.
Synthesis
Ifosfamide, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-
oxazaphosphorin-2-oxide (30.2.1.17), which is viewed as an isomeric compound of
cyclophosphamide (30.2.1.15) and which is analogous in terms of action, is made by reacting N-(2-chloroethyl)-N-(3-hydroxypropyl)amine with phosphorous oxychloride, giving
3-(2-chloroethyl)-2-chlorotetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide (30.2.1.16),
which is reacted with N-(2-chloroethyl)amine, forming the desired ifosfamide (30.2.1.17).
Veterinary Drugs and Treatments
In small animals, ifosfamide may be of benefit as part of treatment
protocols for a variety of neoplasms. Treatment of lymphomas and
soft tissue sarcomas with ifosfamide in dogs and cats has been investigated
to some extent; some efficacy has been demonstrated.
In humans, ifosfamide is used in various treatment protocols for
testicular neoplasms, bone and soft tissue sarcomas, bladder cancer,
lung cancer, cervical cancer, ovarian cancer, and some types of
lymphomas.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhanced effect of
coumarins.
Antipsychotics: avoid concomitant use with
clozapine (increased risk of agranulocytosis).
Metabolism
The pharmacokinetics of ifosfamide are reported to
exhibit considerable inter-individual variation. It is
a prodrug that is extensively metabolised, chiefly by
cytochrome P450 isoenzymes CYP3A4 and CYP2B6 in
the liver, to both active and inactive alkylating metabolites;
there is some evidence that metabolism is saturated
at very high doses. After repeated doses (fractionated
therapy) there is a decrease in the elimination half-life,
apparently due to auto-induction of metabolism. It is
excreted largely in urine, as unchanged drug (80%) and
metabolites.
References
[1] Patent: US4684742, 1987, A
