| |
Ifosfamide (IF) is a widely used antitumor prodrug that is effective against solid tumors such as
sarcomas and hematologic malignancies. Major clinical toxicities include urotoxicity, nephrotoxicity
and neurotoxicity (occurs in approximately 20% of patients). On the other hand, IF has lower myelotoxicity
relative to its structural analog, cyclophosphamide. Glomerular and tubular dysfunctions represent
serious side effects, especially in children who are co-treated with other nephrotoxic drugs. This
diagram, which shows the genes involved in the biotransformations of IF and its metabolites, includes
pathways of activation, deactivation and toxicity. The metabolism of IF is parallel to that of
cyclophosphamide but with some differences in isozyme specificities and reaction kinetics. Activation
of IF to 4-hydroxyifosfamide is catalyzed by the hepatic cytochrome P450 (CYP) isoform CYP3A4 with 2A6,
2B6, 2C8, 2C9 and 2C19 making more minor contributions. Competing with 4-hydroxylation is a major
(up to 50% or more) oxidative pathway that results in dechloroethylation and the formation of chloroacetaldehyde
(neurotoxic) and 2- or 3-dechloroethylifosfamide (primarily mediated by CYP2B6 and CYP3A4).
4-Hydroxyifosfamide rapidly interconverts with its tautomer, aldoifosfamide. It is likely that both of
these metabolites passively diffuse out of hepatic cells, circulate, and then passively enter other
cells. Aldoifosfamide partitions between ALDH1A1-mediated detoxification to carboxyifosfamide and a
spontaneous (non-enzymatic) elimination reaction to yield isophosphoramide mustard (IPM) and acrolein
(associated with bladder toxicity). IPM, the DNA crosslinking agent of clinical significance, is a
circulating metabolite but the anionic IPM does not enter cells as readily as its metabolic precursors.
Thus, the intracellular generation of IPM from aldoifosfamide is generally believed to be important to
a therapeutic result. Multiple IF metabolites can react with glutathione (GSH) resulting in the formation
of various conjugates at different sites along the pathway. Some of these reactions with GSH may be
reversible while others are irreversible; the latter are associated with detoxification pathways.
Large interpatient differences, which may be up to seven-fold, in the pharmacokinetics and biotransformation
of IF have been reported; however, there has been little reported about genetic variations that may
influence varied response to IF treatment. Like cyclophosphamide, IF is chiral at phosphorus but unlike the
case for cyclophosphamide, enantioselectivity in IF metabolism may have clinical significance. This
is particularly relevant to the distribution of 4-hydroxylation versus N-dechloroethylation products
and the impact of this on the CNS toxicity associated with IF therapy. The differences in the metabolism
and disposition of the R- and S-enantiomers of IF have not been fully evaluated in human tissues. Nevertheless,
in several studies using characterized human liver microsomes or cDNA-expressed isozymes it has been shown
that (R)-IF is subject to less dechloroethylation and more rapid 4-hydroxylation relative to the (S)-IF.
|
| Sunita Shukla (PAAR), Susan M. Ludeman,
Jackie Ramirez (PAAR), Norman E. Sladek, David Flockhart (COBRA), Zeruesenay Desta (COBRA), Anne Nguyen (COBRA),
Sharon Marsh (CREATE), Caroline Thorn (PharmGKB), Howard McLeod (CREATE), Irving Wainer (NIH), M. Eileen Dolan (PAAR)
|
| January 18, 2005 |
| August 1, 2007 |
|
