The observation that tumours overexpressed phosphoramidases led to attempts to create an oxazaphosphorine that could be selectively cleaved by phosphoramidases within tumour cells, leading to the synthesis of cyclophosphamide. Subsequently, two other oxazapho-sphorines were synthesized—ifosfamide and trophosphamide. By the 1960s it became apparent these drugs were not activated within tumours but within the liver.
It appears that the oxazaphosphorines are hydroxylated by Cytochrome P450 to the 4-hydroxy compound that is probably the transport form of the drug. 4-hydroxy compounds undergo a series of complex intracellular degradation to form the active mustard.
Cyclophosphamide is extensively used in cytotoxic chemotherapy. It is well absorbed and has nearly 100% bioavailability. Its major toxicities are:
As a result of its relative lack of non-haematological toxicities, it is used in high-dose chemotherapy regimens.
Ifosfamide is an isomer of cyclophosphamide. In addition to the usual pathway of 4 hydroxylation, a significant proportion of the ifosfamide dosage can be N-dealkylated, liberating chloroacetaldehyde, that is thought to be responsible for some of the toxicity profile.
Ifosfamide nearly always causes alopecia and haemorrhagic cystitis, but this can be circumvented by co-administration of thiol mesna which is thought to chemically combine with acrolein, the metabolite thought to be responsible for this toxicity. Ifosfamide can also cause encephalopathy; this is more common with oral administration.
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