The effect of route of administration and fractionation of dose on the metabolism of ifosfamide

Lind, Michael; Roberts, Helene; Thatcher, Nick; Idle, Jeffrey R.

doi:10.1007/bf02897254

Cited by 53 publications

(21 citation statements)

References 12 publications

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“…In fact, our results for total urinary excretion of urine metabolites are almost identical to those of Boddy and Idle (1992), who used the same method. An earlier study found only 9% of administered dose in the urine (Lind et al, 1990).…”

Section: Discussionmentioning

confidence: 86%

Metabolism of ifosfamide during a 3 day infusion

Hartley

Hansen²,

Harland³

et al. 1994

Br J Cancer

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Summary Urinary drug metabolites were measured in 21 patients receiving ifosfamide by continuous infusion over 3 days. Mean values for the proportion of drug excreted as parent compound, 2-dechloroethylifosfamide (2-DC), 3-dechloroethylifosfamide (3-DC), carboxyifosfamide (CX) and ifosforamide mustard (IPM) were 19, 6, 10, 7 and 8% of dose respectively. The proportion of urinary drug products in the form of ifosfamide fell considerably over the course of the 3 days. This was mirrored by an increase in the proportion of 2-DC, 3 al., 1974;Sladek, 1988) (see Figure 1 for a summary of the metabolic pathways). Ifosfamide is converted to its active intermediate (4-OH-IFOS) by the cytochrome P450 enzymes (Connors et al., 1974). There is evidence for enzyme induction by repeated administration (Nelson et al., 1976;Piazza et al., 1984;Wagner & Drings, 1986;Lind et al., 1989;Lewis et al., 1990), and this may alter the proportions of metabolites formed. Toxicity is common and may be severe. Whereas some sideeffects -myelosuppression and alopecia -are related to the tumoricidal metabolite ifosforamide mustard, other toxicities appear to be due to other products. Bladder toxicity and nephrotoxicity are almost certainly caused by acrolein (Brock et al., 1981), formed in equimolar amounts with ifosforamide mustard (Alarcon et al., 1972). The cause of the neurotoxicity seen following ifosfamide therapy is less certain, but it may be related to chloroacetaldehyde formed during the loss of the chloroethyl moieties (Norpoth, 1976;Goren et al., 1986). This compound could also contribute to renal damage (Skinner et al., 1993). The co-products of these pathways are 2-dechloro-and 3-dechloroifosfamide. Clearly, the efficacy and toxicity of ifosfamide will relate to the activity of the products of not only the above pathways, but also other inactivating pathways, notably 4-keto ifosfamide and carboxyifosfamide.Despite its importance, there are very few quantitative data on ifosfamide metabolism. The purpose of the present study was to determine the patterns of excretion and amounts of urinary metabolites during IFOS therapy both during single treatment cycles and in the same patients undergoing repetitive treatments. Materials and methodsThe parent drug, ifosfamide (IFOS), and its metabolites (2-chloroethyl)-2-amino-tetrahydro-2-oxide-2H-1,3,2-oxazaphosphorine, (2 dechloroethylifosfamide, 2DC), 2-(2-chloroethyl)-amino-tetrahydro-2-oxide-2H-1,3,2-oxazaphosphorine, (3-dechloroethylifosfamide 3DC), 3-[N,N'-bis(2-chloroethylamino)phosphinyloxy] propanic acid (carboxyifosfamide, CX) and N,N'-bis(2-chloroethyl)phosphorodiamidic acid (isophosphoramide mustard, IPM) were all prepared, authenticated and kindly given by Asta Medica (Frankfurt, Germany). The keto metabolite, when seen in patients' urine, was present in amounts near the limit of detection and so these are not reported here.Sodium acetate, potassium hydroxide and 4-(4-nitrobenzyl)pyridine (NBP) were all obtained from Sigma. Methanol and acetone for development of the NBP reagent w...

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Section: Discussionmentioning

confidence: 86%

Metabolism of ifosfamide during a 3 day infusion

Hartley

Hansen²,

Harland³

et al. 1994

Br J Cancer

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“…For this study we used a continuous infusion over three days because of a low reported incidence of haemorrhagic cystitis and myelosuppression compared with other schedules (Cerny et al, 1990;Lind et al, 1990). No instances of haemorrhagic cystitis were observed in this study but myelosuppression was common and dose-limiting as expected.…”

Section: Discussionmentioning

confidence: 85%

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer

et al. 2002

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The aim of this study was to determine the maximum tolerated dose of a fixed dose of docetaxel when combined with continuous infusion ifosfamide, with and without G-CSF support, in the treatment of advanced cancer, and to evaluate antitumour activity of this combination. Thirty-one patients with advanced malignancies were treated with docetaxel 75 mg/m 2 intravenously on days 1, and ifosfamide at increasing dose levels from 1500 mg/m 2 /day to 2750 mg/m 2 /day as a continuous infusion from day 1 -3, every 3 weeks. A total of 107 cycles of treatment were administered. Without G-CSF support doselimiting toxicity of grade 4 neutropenia greater than 5 days duration occurred at dose level 1. With the addition of G-CSF the maximum tolerated dose was docetaxel 75 mg/m 2 on day 1 and ifosfamide 2750 mg/m 2 /day on days 1 -3. Dose limiting toxicity (DLT) included ifosfamide-induced encephalopathy, febrile neutropenia and grade three mucositis. Three complete responses and 3 partial responses were seen. This combination of docetaxel and infusional ifosfamide is feasible and effective. The recommended dose for future phase II studies is docetaxel 75 mg/m 2 on day 1 and ifosfamide 2500 mg/m 2 /day continuous infusion on days 1 -3.

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“…The hepatic metabolism of IF has been extensively studied and occurs in the liver by two major pathways, Fig. 1 [6][7][8][9][10][11]. One pathway involves the 4-hydroxylation of IF and eventually leads to the production of the cytotoxic isophosphoramide mustard [6].…”

Section: Introductionmentioning

confidence: 99%

“…Clinically, the N-dechloroethylation pathway has been associated with treatment-ending central nervous system (CNS) toxicity [5,[7][8][9]. The N-dechloroethylation pathway is regioselective and enantioselective [10,11] and, as a result, (R)-IF and (S)-IF have distinct efficacy and toxicity profiles.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective liquid chromatography–mass spectrometry assay for the determination of ifosfamide and identification of the N-dechloroethylated metabolites of ifosfamide in human plasma

Oliveira

Onorato

Siluk

et al. 2007

Journal of Pharmaceutical and Biomedical Analysis

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The lower limit of detection (LLOD) was 5.00 ng/ml. The inter-and intra-day precision ranged from 3.63 to 15.8 % relative standard deviation (RSD) and 10.1 to 14.3 % RSD, respectively, and the accuracy ranged from 89.2 to 101.5 % of the nominal values. The method was applied to the analysis of plasma samples obtained from a cancer patient who received 3.75 g/m 2 /d dose of (R,S)-ifosfamide as a 96-h continuous infusion.

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The effect of route of administration and fractionation of dose on the metabolism of ifosfamide

Cited by 53 publications

References 12 publications

Metabolism of ifosfamide during a 3 day infusion

Metabolism of ifosfamide during a 3 day infusion

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer

Enantioselective liquid chromatography–mass spectrometry assay for the determination of ifosfamide and identification of the N-dechloroethylated metabolites of ifosfamide in human plasma

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