Ifosfamide

Indications

Ifosfamide is utilized as part of several chemotherapeutic protocols, primarily as a third-line treatment for recurrent or refractory germ cell testicular cancer. It is also indicated for use in treating cervical cancer, where it is often combined with surgery and/or radiation therapy. Additionally, Ifosfamide is employed in the management of various soft tissue sarcomas, osteosarcoma, bladder cancer, ovarian cancer, small cell lung cancer, and non-Hodgkin's lymphoma.

Pharmacodynamics

To exert its cytotoxic effects, Ifosfamide requires metabolic activation by liver microsomal enzymes. This activation involves hydroxylation at the ring carbon atom 4, forming the unstable intermediate, 4-hydroxyifosfamide. This intermediate rapidly degrades to the stable urinary metabolite, 4-ketoifosfamide. Further opening of the ring results in the formation of 4-carboxyifosfamide, which, along with other urinary metabolites such as ifosphoramide and acrolein, is not cytotoxic. The active, DNA-interacting species are alkylated metabolites resulting from enzymatic oxidation and dealkylation of the chloroethyl side chains. Notably, Ifosfamide is a cycle-phase nonspecific agent.

Metabolism

Ifosfamide undergoes extensive, primarily hepatic metabolism via two distinct pathways. The primary pathway involves ring oxidation ("activation") to produce the active metabolite, 4-hydroxy-ifosfamide. The secondary pathway entails side-chain oxidation, leading to the formation of inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide, with the release of the toxic by-product, chloroacetaldehyde. Trace amounts of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. While metabolism is critical for generating active forms of the drug, it exhibits significant variability among patients.

Mechanism of Action

The precise mechanism of action for Ifosfamide has not been fully elucidated, but it is believed to function similarly to other alkylating agents. Ifosfamide undergoes metabolic activation in the liver through enzymes of the cytochrome P450 system. Once activated, its metabolites interact with various intracellular molecules, notably nucleic acids. The primary cytotoxic effect results from DNA alkylation, as the active metabolites bind to the N-7 position of guanine, creating reactive electrophilic groups. This process leads to the formation of interstrand and intrastrand DNA cross-links, ultimately causing cell death.