CLINICAL PHARMACOLOGY
CYTOXAN (cyclophosphamide) is biotransformed principally
in the liver to active alkylating metabolites by a mined
function microsomal oxidase system. These metabolites
interfere with the growth of susceptible rapidly proliferating
malignant cells. The mechanism of action is thought to
involve cross-linking of tumor cell DNA.
CYTOXAN is well absorbed after oral administration with
a bioavailability greater than 75%. The unchanged drug
has an elimination half-life of 3 to 12 hours. It is eliminated
primarily in the form of metabolites, but from 5 to 25%
of the dose is excreted in urine as unchanged drug. Several
cytotoxic and noncytotoxic metabolites have been identified
in urine and in plasma. Concentrations of metabolites
reach a maximum in plasma 2 to 3 hours after an intravenous
dose. Plasma protein binding of unchanged drug is low
but some metabolites are bound to an extent greater than
60%. It has not been demonstrated that any single metabolite
is responsible for either the therapeutic or toxic effects
of cyclophosphamide. Although elevated levels of metabolites
of cyclophosphamide have been observed in patients with
renal failure, increased clinical toxicity in such patients
has not been demonstrated.
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