Ifosfamide Clinical Pharmacokinetics

Abstract

This article reviews the metabolism and pharmacokinetics of ifosfamide and their implications for the cytostatic efficacy and toxicity pattern of this alkylating agent. Ifosfamide is a prodrug that requires biotransformation to become cytotoxic. It is a structural isomer of cyclophosphamide from which it differs only in having the chlorethyl functions on different nitrogen atoms. This causes a considerable change in initial metabolism, although overall metabolism remains the same. Beside the formation of 4-hydroxy-ifosfamide ('activated ifosfamide'), a second pathway with liberation of chloroacetaldehyde exists. Therefore, less activated drug is formed than during cyclophosphamide metabolism. This fact may well explain why higher doses of ifosfamide are required during treatment. Chloroacetaldehyde may account for the adverse effects and therapeutic effects of the parent drug. This metabolite has been associated with central nervous system toxicity during ifosfamide treatment and was shown to deplete intracellular glutathione concentrations. Glutathione depletion may support the activity of alkylating metabolites in tumour cells, thus overcoming the relative resistance of the cells to alkylating agents. Possibly, this mechanism explains the lack of complete cross-resistance between ifosfamide and cyclophosphamide as well as the greater antitumour activity of ifosfamide in some tumours. Urotoxicity of ifosfamide, which was the dose-limiting adverse effect, can be successfully attenuated by the use of mesna. Distinct pharmacokinetic properties of mesna are responsible for the fact that in contrast to other sulphydryl compounds the uroprotective activity of mesna does not imply a loss of therapeutic efficacy.

A model of hemorrhagic cystitis induced with acrolein in mice

“…The profile of HC observed after ACR administration was similar to that observed when CYP or IFS was administered to mice (15) or rats (12). This fact, taken together with the demonstration that ACR is found in the urine of humans (16) and of experimental animals treated with CYP or IFS (17), as described in the literature (5,14,18,19), indicate that ACR is the urine metabolite responsible for the HC observed after oxazaphos- phorine treatment.…”

Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis - comparison of the effects of dexamethasone and Mesna

“…The administration of systemic Mesna results in regional detoxication of the urinary system (8,9). The interaction between acrolein and Mesna results in an inactive compound (10). Thus, Mesna is indicated to prevent the occurrence of hemorrhagic cystitis, but is not effective when the lesion has been established.…”

The pharmacokinetics and metabolism of ifosfamide during bolus and infusional administration: a randomized cross-over study

“…Previous pharmacokinetic studies have been reviewed recently by Wagner (1994) and Kaijser et al (1994). A number of studies were performed on patients who received either infusional or bolus IFOS, but which measured only the parent drug (Creaven et al, 1974;Allen and Creaven, 1975;Nelson et al, 1976).…”

“…The metabolites responsible for nephrotoxicity and neurotoxicity are unknown, although CAA has been implicated as this is a reactive metabolite and produced in large quantities (Wagner, 1994). Concentrations of 2DC and 3DC are an indirect measurement of the unstable metabolite CAA, as this is formed in equimolar amounts in the N-dechloroethylation process.…”

“…Some of this variability may be due to the differences in detection method (Nelson et al, 1976;Wagner et al, 1994), the schedule of administration, schedules, age (Lind et al, 1989a), the volume of distribution (Lind et al, 1989b), and the patient's age and hepatic and renal function. Metabolic factors may also be responsible such as genetic differences in the mixed function oxidases or drug interactions involving the cytochrome P450 systems (Lind et al, 1990;Kaijser et al, 1993;1994;Kurowski & Wagner, 1993).…”