Fosfa Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Ifosfamide has been shown to require metabolic activation by microsomal liver enzymes to produce biologically active metabolites. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. Opening of the ring results in formation of the stable urinary metabolite 4-carboxyifosfamide. These urinary metabolites have not been found to be cytotoxic. N,N-bis(2-chloroethyl)-phosphoric acid diamide (Ifosphoramide) and acrolein are also found. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation produces the major urinary metabolites, dechloroethyl Ifosfamide and dechloroethyl cyclophosphamide. The alkylated metabolites of Ifosfamide have been shown to interact with DNA. In vitro incubation of DNA with activated Ifosfamide has produced phosphotriesters. The treatment of intact cell nuclei may also result in the formation of DNA-DNA cross-links. DNA repair most likely occurs in G1 and G2 stage cells.
Pharmacokinetics: Ifosfamide is well absorbed from the gastrointestinal tract. The pharmacokinetics of ifosfamide are reported to exhibit considerable interindividual variation. It is a prodrug that is extensively metabolised, chiefly by cytochrome P450 isoenzymes such as CYP3A4 and CYP2B6 in the liver, to a variety of active and inactive metabolites; there is some evidence that metabolism is saturated at very high doses. Although the manufacturers state that a mean terminal elimination half-life of about 15 hours has been reported after a single high dose intravenous bolus, most studies at lower doses appear to have recorded elimination half-lives of about 4 to 8 hours. After repeated doses (fractionated therapy) there is a decrease in the elimination half-life, apparently due to autoinduction of metabolism. Ifosfamide is distributed into the CSF. It is excreted largely in urine, as unchanged drug and metabolites.