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...
Summary In a randomized cross-over trial, 11 patients received ifosfamide (IFOS) in 21-day cycles, which alternated between 3 g m-2 x (2 or 3) days given as a 1-h bolus doses, or the same total dose as a continuous infusion. Patients who received four or more cycles also alternated between two cycles on dexamethasone 4 mg 8 hourly for 3 days starting 8 h before IFOS, and two cycles off dexamethasone. A total of 34 patient cycles were studied and serum and urinary levels of IFOS, 2 dechloroethylifosfamide (2DC), 3 dechloroethylifosfamide (3DC), carboxyifosfamide (CX) and isophosphoramide mustard (IPM) were measured by thin-layer chromatography. No significant differences could be detected in the areas under the curve (AUCs) of serum concentration, nor in the proportion of IFOS or its metabolites found in the urine. There was no significant effect of dexamethasone on IFOS metabolism. These results indicate that there is no identifiable pharmacokinetic basis for insistence on either bolus or infusional methods of IFOS administration.
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