Ifosfamide

Ifosfamide (50 mM) increases CYP3A4, CYP2C8, and CYP2C9 protein levels in hepatocytes, which thereby enhances their own rates of 4-hydroxylation in the cultured hepatocytes. Ifosfamide only induces CYP3A4 in one human hepatocyte culture that contained the polymorphically expressed CYP3A5 in addition to the more widely expressed CYP3A4. ^[1] Ifosfamide is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Ifosfamide has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin's and Hodgkin's lymphoma, and ovarian cancer. ^[2] Ifosfamide is highly cytotoxic to MCF-7 cells following stable transfection of CYP2B1 but exhibits no toxicity to parental tumor cells or to a beta-galactosidase-expressing MCF-7 transfectant, this cytotoxicity could be appreciably blocked by the CYP2B1 inhibitor metyrapone. ^[3] Ifosfamide combined with Zoledronic acid is more effective than each agent alone in preventing tumor recurrence, improving tissue repair, and increasing bone formation as revealed by the analysis of trabecular architecture. ^[4]

Ifosfamide (100 mg/kg, 200 mg/kg and 400 mg/kg) injected intraperitoneally induces a dose dependent increase in bladder wet weight and Evans blue extravasation in mice. Ifosfamide reveals extensive cystitis characterized by acute inflammation with vascular congestion, edema, hemorrhage and fibrin deposition, neutrophil cell infiltration and epithelial denudation in mice. Ifosfamide shows intense reactivity to inducible nitric oxide synthase in the cytoplasm as well as intense and diffuse necrosis on hematoxylin and eosin staining. ^[5]