Pharmacokinetics of ifosfamide

Abstract

A multicompartment pharmacokinetic model for ifosfamide has been employed using a system of first-order differential equations, which includes a term for metabolism according to Michaelis-Menten kinetics in order to describe the distribution and elimination parameters of ifosfamide in man. The model satisfactorily accounts for all the administered drug. The pseudometabolic rate constant for ifosfamide in man is found to be less than 20 percent of that reported for cyclophosphamide in man, in agreement with the more extensive metabolism of cyclophosphamide than ifosfamide. A number of the pharmacokinetic parameters for ifosfamide differ substantially from those reported for cyclophosphamide. The volume of distribution for ifosfamide metabolites was found to be approximately equal to the plasma space volume. The central compartment volume for intact ifosfamide is slightly larger than for cyclophosphamide and includes the easily diffusible extravascular space of the body and suggests lack of protein binding. The renal clearance of ifosfamide is low and about twice that of cyclophosphamide. The model indicates that only a small fraction of the total metabolites distribute into the peripheral compartment and suggests that multiple doses of the drug may be useful.

Oxazaphosphorine bioactivation and detoxification: the role of xenobiotic receptors

“…Developed as an analogue of CPA, IFO only differs chemically from CPA by one chloroethyl group transpositioned from the mustard nitrogen to the ring nitrogen 21 . Like CPA, IFO also requires CYP-mediated metabolism to produce active alkylating moieties before manifesting its antitumor effects 22; 23 . Clinically, IFO has been used in young adult and pediatric tumors along with other chemotherapeutics in adjuvant treatment.…”

Pharmacokinetics of ifosfamide and its enantiomers following a single 1 h intravenous infusion of the racemate in patients with small cell lung carcinoma.

“…Racemic ifosfamide shows little plasma protein binding [17]. The similarities in the volumes of distribution of the enantiomers indicate a lack of stereo-specificity in their distribution.…”

Design of New Oxazaphosphorine Anticancer Drugs

“…The metabolism of CPA, IFO and trofosfamide is similar with all of them being activated through 4-hydroxylation by hepatic cytochrome P450s (CYPs) such as CYP2B6 and CYP3A4 [88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104], yielding cytotoxic nitrogen mustards. They are deactivated via side chain oxidation (N-dechloroethylation), giving rise to toxic byproducts, such as neurotoxic and nephrotoxic chloroacetaldehyde (CAA) and urotoxic acrolein (for the metabolism of CPA in humans, see Fig.…”