Ifosfamide   中文名称: 异环磷酰胺

DNA Alkylator

体外活性：Ifosfamide (50 mM) 增加肝细胞中 CYP3A4、CYP2C8 和 CYP2C9 蛋白水平，从而提高培养肝细胞中自身的 4-羟基化率。异环磷酰胺仅在一种人肝细胞培养物中诱导 CYP3A4，该培养物除了更广泛表达的 CYP3A4 之外还含有多态性表达的 CYP3A5。异环磷酰胺是一种前药，在肝脏中通过细胞色素 P450 混合功能氧化酶代谢为活性烷基化化合物异磷酰胺芥子。异环磷酰胺在小细胞肺癌、儿科实体瘤、非霍奇金和霍奇金淋巴瘤以及卵巢癌中产生了良好的缓解率。稳定转染 CYP2B1 后，异环磷酰胺对 MCF-7 细胞具有高度细胞毒性，但对亲代肿瘤细胞或表达 β-半乳糖苷酶的 MCF-7 转染子没有毒性，这种细胞毒性可以被 CYP2B1 抑制剂甲替拉酮明显阻断。小梁结构分析显示，异环磷酰胺与唑来膦酸联合使用比单独使用每种药物在预防肿瘤复发、改善组织修复和增加骨形成方面更有效。

腹腔注射异环磷酰胺（100 mg/kg、200 mg/kg 和 400 mg/kg）可引起小鼠膀胱湿重和伊文思蓝外渗的剂量依赖性增加。异环磷酰胺显示小鼠广泛性膀胱炎，其特征是急性炎症，伴有血管充血、水肿、出血和纤维蛋白沉积、中性粒细胞浸润和上皮剥脱。异环磷酰胺对细胞质中的诱导型一氧化氮合酶表现出强烈的反应性，并且在苏木精和伊红染色中显示出强烈的弥漫性坏死。

使用含有 2 毫升的培养基将 4 × 10⁴ 细胞接种到 3 cm 培养皿中。当达到终浓度时，第二天添加 0 至 5 mM 异环磷酰胺。除去培养基并用 PBS 清洁细胞并进行计数或染色后，还需要六天的时间[2]。

Rats: Female rats are separated into four groups of eight before mating: group 1 is an untreated negative control group; group 2 is an injection of 1 mL of 0.9% NaCl; group 3 is an injection of 25 mg/kg Ifosfamide; and group 4 is an injection of 50 mg/kg Ifosfamide. Following five days of daily injections of Ifosfamide, three females are kept in a cage with one untreated male for a maximum of one week. Every day, vaginal smears are checked to see if someone is pregnant. In the event that sperm are found, the first 24 hours after mating are considered the first day of pregnancy. The expectant mothers are kept apart and regularly checked for symptoms of toxicity and miscarriage. On the eighteenth day of gestation, all pregnant animals are sacrificed by being beheaded. Serum is decanted and kept at -70°C until it is needed for the hormone assay. Cardiac blood (2.5–3 mL/rat) is collected in nonheparinized test tubes, centrifuged at 3,000× g for 30 min. The uterus and both ovaries are removed after blood collection, cleaned in saline solution, and the corpora lutea of pregnancy are counted visually. Each uterine horn is then examined to determine the number of viable fetuses, implantation sites, and resorption sites. Crown rump (CR) length is measured, weight is recorded, and each fetus is extracted from its umbilical cord. The placental weights are noted and the fetuses are inspected for external malformation. In order to facilitate histological and immunohistochemical analysis, fetuses and placentas from the control and treated groups are fixed in 10% neutral broth formalin.

Absorption, Distribution and Excretion
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.
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.
2.4±0.33 L/h/m^2 [pediatric patients]
Renal excretion & t1/2 are dose & schedule dependent. 60-80% recovered as unchanged drug or metabolite in urine within 72 hr after admin.
The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m(2)/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (+/-sem) in vitro and in vivo erythrocyte (e)-plasma (p) partition coefficients (P(e/p)) were 0.75+/-0.01 and 0.81+/-0.03, 0.62+/-0.09 and 0.73+/-0.05, 0.76+/-0.10 and 0.93+/-0.05 and 1.38+/-0.04 and 0.98+/-0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUC(e/p)) were 0.96+/-0.03, 0.87+/-0.07, 0.98+/-0.06 and 1.34+/-0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic-pharmacodynamic studies.
... To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours. ... Pharmacokinetic assessment followed by model fitting. Patients: The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m2 in 1 or 3 hours on 1, 2 or 3 days. ... A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy-ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. ... Population values (mean +/- standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/h/m2 and 20.6 +/- 1.6 L/m2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h2/m2. The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0.0083 m2/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. ... We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.
... The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. ... Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling. ... The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.
For more Absorption, Distribution and Excretion (Complete) data for IFOSFAMIDE (6 total), please visit the HSDB record page.

---

Metabolism / Metabolites
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.
Like cyclophosphamide, ifosfamide is activated in the liver by hydroxylation. However, the activation of ifosfamide proceeds more slowly, with greater production of dechlorinated metabolites & chloroacetaldehyde. These differences in metabolism likely account for the higher doses of ifosfamide required for equitoxic effects & the possible difference in antitumor spectrum of the two agents.
Like cyclophosphamide, isophosphamide requires metabolism by microsomal enzymes to act as a cytotoxic agent. It is rapidly metabolized in many species, including rodents and dogs; the urinary metabolites indicate that a series of reactions take place analogous to those in the metabolism of cyclophosphamide. Acrolein is produced during its oxidative degradation, and one product of the reaction is the ring-opened carboxy derivative. Dogs also rapidly metabolize isophosphamide, and the carboxy derivative and 4-keto isophosphamide have been identified in the urine.
The aim of this study was to develop a population pharmacokinetic model that could describe the pharmacokinetics of ifosfamide. 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide, and calculate their plasma exposure and urinary excretion. A group of 14 patients with small-cell lung cancer received a 1-h intravenous infusion of 2.0 or 3.0 g/m2 ifosfamide over 1 or 2 days in combination with 175 mg/m2 paclitaxel and carboplatin at AUC 6. The concentration-time profiles of ifosfamide were described by an ifosfamide concentration-dependent development of autoinduction of ifosfamide clearance. Metabolite compartments were linked to the ifosfamide compartment enabling description of the concentration-time profiles of 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide. The Bayesian estimates of the pharmacokinetic parameters were used to calculate the systemic exposure to ifosfamide and its metabolites for the four ifosfamide schedules. Fractionation of the dose over 2 days resulted increased metabolite formation, especially of 2-dechloroethylifosfamide, probably due to increased autoinduction. Renal recovery was only minor with 6.6% of the administered dose excreted unchanged and 9.8% as dechloroethylated metabolites. In conclusion, ifosfamide pharmacokinetics were described with an ifosfamide concentration-dependent development of autoinduction and allowed estimation of the population pharmacokinetics of the metabolites of ifosfamide. Fractionation of the dose resulted in increased exposure to 2-dechloroethylifosfamide, probably due to increased autoinduction.
The anticancer drug ifosfamide is a prodrug requiring activation through 4-hydroxyifosfamide to ifosforamide mustard, to exert cytotoxicity. Deactivation of ifosfamide leads to 2- and 3-dechloroethylifosfamide and the release of potentially neurotoxic chloracetaldehyde. The aim of this study was to quantify and to compare the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide, 4-hydroxyifosfamide, and ifosforamide mustard in short (1-4 h), medium (24-72 h), and long infusion durations (96-240 h) of ifosfamide. An integrated population pharmacokinetic model was used to describe the autoinducible pharmacokinetics of ifosfamide and its four metabolites in 56 patients. The rate by which autoinduction of the metabolism of ifosfamide developed was found to be significantly dependent on the infusion schedule. The rate was 52% lower with long infusion durations compared with short infusion durations. This difference was, however, comparable with its interindividual variability (22%) and was, therefore, considered to be of minor clinical importance. Autoinduction caused a less than proportional increase in the area under the ifosfamide plasma concentration-time curve (AUC) and more than proportional increase in metabolite exposure with increasing ifosfamide dose. During long infusion durations dose-corrected exposures (AUC/D) were significantly decreased for ifosfamide and increased for 3-dechloroethylifosfamide compared with short infusion durations. No differences in dose-normalized exposure to ifosfamide and metabolites were observed between short and medium infusion durations. This study demonstrates that the duration of ifosfamide infusion influences the exposure to the parent and its metabolite 3-dechloroethylifosfamide. The observed dose and infusion duration dependence should be taken into account when modeling ifosfamide metabolism.
Ifosfamide is a known human metabolite of L-trofosfamide.
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.

---

Biological Half-Life
7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.
The elimination half-life associated with doses of 2.5 g/sq m is 6-8 hr, whereas the elimination half-life associated with doses of 3.5-5 g/sq m is 14-16 hr.

Toxicity Summary
After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis.

---

Hepatotoxicity
The toxicity of ifosfamide seems to be similar to that of cyclophosphamide. Mild and transient elevations in serum aminotransferase levels are found in a high proportion of patients receiving ifosfamide. Because ifosfamide is typically given in combination with other antineoplastic agents, its role in causing the serum enzyme elevations is often not clear. The abnormalities are generally transient, do not cause symptoms and do not require dose modification. Clinically apparent liver injury from ifosfamide has been limited to a small number of cases of cholestatic hepatitis arising within a few weeks of receiving ifosfamide (with other antineoplastic agents). In addition, sinusoidal obstruction syndrome has been reported after conditioning regimens that have included ifosfamide in preparation for hematopoietic cell transplantation. The onset of injury is usually within one to three weeks of the myeloablation and is characterized by a sudden onset of abdominal pain, weight gain, ascites, marked increase in serum aminotransferase levels (and lactic dehydrogenase), and subsequent jaundice and hepatic dysfunction. The severity of sinusoidal obstruction syndrome varies from a transient, self limited injury to acute liver failure. The diagnosis is usually based on clinical features of tenderness and enlargement of the liver, weight gain, ascites and jaundice. Liver biopsy is diagnostic but often contraindicated, because of severe thrombocytopenia after bone marrow transplantation.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, especially alkylating agents such as ifosfamide. Labeling suggests that mothers should not breastfeed during therapy and for 1 week after the last dose of ifosfamide or mesna. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Ifosfamide shows little plasma protein binding.

---

Toxicity Data
LD₅₀ (mouse) = 390-1005 mg/kg, LD₅₀ (rat) = 150-190 mg/kg.

---

Interactions
The more urotoxic agent ifosfamide was introduced to the market with the uroprotective agent, Mesna. Mesna liberated free thiol groups in the bladder which then can react with & neutralize the oxazaphosphorine metabolite. When administered in an appropriate dosing schedule, Mesna can prevent the bladder toxicity completely.
BACKGROUND: The autoinducible metabolic transformation of the anticancer agent ifosfamide involves activation through 4-hydroxyifosfamide to the ultimate cytotoxic ifosforamide mustard and deactivation to 2- and 3-dechloroethylifosfamide with concomitant release of the neurotoxic chloroacetaldehyde. Activation is mediated by cytochrome P450 (CYP) 3A4 and deactivation by CYP3A4 and CYP2B6. The aim of this study was to investigate modulation of the CYP-mediated metabolism of ifosfamide with ketoconazole, a potent inhibitor of CYP3A4, and rifampin (INN, rifampicin), an inducer of CYP3A4/CYP2B6. METHODS: In a double-randomized, 2-way crossover study a total of 16 patients received ifosfamide 3 g/m(2) per 24 hours intravenously, either alone or in combination with 200 mg ketoconazole twice daily (1 day before treatment and 3 days of concomitant administration) or 300 mg rifampin twice daily (3 days before treatment and 3 days of concomitant administration). Plasma pharmacokinetics and urinary excretion of ifosfamide, 2- and 3-dechloroethylifosfamide, and 4-hydroxyifosfamide were assessed in both courses. Data analysis was performed with a population pharmacokinetic model with a description of autoinduction of ifosfamide. RESULTS: Rifampin increased the clearance of ifosfamide at the start of therapy at 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, whereas exposure to the metabolites was decreased as a result of increased elimination. The fraction metabolized and the exposure to 4-hydroxyifosfamide were not significantly influenced. Ketoconazole did not affect the fraction metabolized or the exposure to the dechloroethylated metabolites, whereas both parameters were reduced with 4-hydroxyifosfamide. CONCLUSIONS: Coadministration of ifosfamide with ketoconazole or rifampin did not produce changes in the pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamide therapy.
Leukopenic and/or thrombocytopenic effects of ifosfamide may be increased with concurrent or recent therapy if these medications /blood dyscarasia-causing medications/ cause the same effects; dosage adjustments of ifosfamide, if necessary, should be based on blood counts.
Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with ifosfamide/.
For more Interactions (Complete) data for IFOSFAMIDE (7 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Rat oral 143 mg/kg
LD50 Rat ip 140 mg/kg
LD50 Rat sc 160 mg/kg
LD50 Rat iv 190 mg/kg
For more Non-Human Toxicity Values (Complete) data for IFOSFAMIDE (8 total), please visit the HSDB record page.

[1]. Cancer Res . 1997 May 15;57(10):1946-54.

[2]. Drugs . 1991 Sep;42(3):428-67.

[3]. Cancer Res . 1996 Mar 15;56(6):1331-40.

[4]. Bone . 2005 Jul;37(1):74-86.

[5]. Urol . 2002 May;167(5):2229-34.

Therapeutic Uses
Ifosfamide currently is approved for use in combination with other drugs for germ cell testicular cancer & is widely used to treat pediatric & adult sarcomas. Clinical trials also have shown ifosfamide to be active against carcinomas of the cervix & lung & against lymphomas. It is a common component of high-dose chemotherapy regimens with bone marrow or stem cell rescue; in these regimens, in total doses of 12-14 g/sq m, it may cause severe neurological toxicity, including coma & death. This toxicity is thought to result form a metabolite, chloracetaldehyde. In addition to hemorrhagic cystitis, ifosfamide causes nausea, vomiting, anorexia, leukopenia, nephrotoxicity, & CNS disturbances (especially somnolence & confusion).
Ifosfamide is indicated, in combination with other antineoplastic agents and a prophylactic agent against hemorrhagic cystitis (such as mesna), for treatment of germ cell testicular tumors. /Included in US product labeling/
Ifosfamide is indicated as reasonable medical therapy for treatment of head and neck carcinoma. (Evidence rating: IIID) /NOT included in US product labeling/
Ifosfamide is used for treatment of soft-tissue sarcomas, Ewing's sarcoma, and Hodgkin's and non-Hodgkin's lymphomas. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for IFOSFAMIDE (9 total), please visit the HSDB record page.

---

Drug Warnings
It is a common component of high-dose chemotherapy regimens with bone marrow or stem cell rescue; in these regimens, in total doses of 12-14 g/sq m, it may cause severe neurological toxicity, including coma & death. This toxicity is thought to result form a metabolite, chloracetaldehyde. In addition to hemorrhagic cystitis, ifosfamide causes nausea, vomiting, anorexia, leukopenia, nephrotoxicity, & CNS disturbances (especially somnolence & confusion).
Ifosfamide is distributed into breast milk. Breast feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).
The bone marrow depressant effects of ifosfamide may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.
Many side effects of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
For more Drug Warnings (Complete) data for IFOSFAMIDE (20 total), please visit the HSDB record page.

---

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.

C7H15CL2N2O2P

261.09

260.024

C, 32.20; H, 5.79; Cl, 27.16; N, 10.73; O, 12.26; P, 11.86

3778-73-2

3690

White to off-white solid powder

1.3±0.1 g/cm3

336.1±52.0 °C at 760 mmHg

48ºC

157.1±30.7 °C

0.0±0.7 mmHg at 25°C

1.506

0.23

51.38

1

4

5

14

218

0

ClC([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])OP1(N([H])C([H])([H])C([H])([H])Cl)=O

HOMGKSMUEGBAAB-UHFFFAOYSA-N

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

N,3-bis(2-chloroethyl)-2-oxo-1,3,2lambda5-oxazaphosphinan-2-amine

NSC-109724; Isophosphamide; Ifomide; NSC 109724; NSC109724; Iphosphamid; iphosphamide; Isoendoxan; IsoEndoxan; isophosphamide; Naxamide; Trade names: Cyfos; Ifex; Ifosfamidum

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.58 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.5 mg/mL (9.58 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (9.58 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

配方 4 中的溶解度: 25 mg/mL (95.75 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。