Metabolism and pharmacokinetics of oxazaphosphorines

The 2 most commonly used oxazaphosphorines are cyclophosphamide and ifosfam ide, although ether bifunctional mustard analogues continue to be investiga ted. The pharmacology of these agents is determined by their metabolism, si nce the parent drug is relatively inactive. For cyclophosphamide, eliminati on of the parent compound is by activation to the 4-hydroxy metabolite, alt hough other minor pathways of inactivation also play a role. Ifosfamide is inactivated to a greater degree by dechloroethylation reactions. More robus t assay methods for the 4-hydroxy metabolites may reveal more about the cli nical pharmacology of these drugs, but at present the best pharmacodynamic data indicate an inverse relationship between plasma concentration of paren t drug and either toxicity or antitumour effect. The metabolism of cyclophosphamide is of particular relevance in the applic ation of high dose chemotherapy. The activation pathway of metabolism is sa turable, such that at higher doses (greater than 2 to 4 g/m(2)) a greater p roportion of the drug is eliminated as inactive metabolites. However, both cyclophosphamide and ifosfamide also act to induce their own metabolism. Si nce most high dose regimens require a continuous infusion or divided doses over several days, saturation of metabolism may be compensated for, in part , by auto-induction. Although a quantitative distinction may be made betwee n the cytochrome P450 isoforms responsible for the activating 4-hydroxylati on reaction and those which mediate the dechloroethylation reactions, selec tive induction of the activation pathway, or inhibition of the inactivating pathway, has not been demonstrated clinically. Mathematical models to describe and predict the relative contributions of s aturation and autoinduction to the net activation of cyclophosphamide have been developed. However, these require careful validation and may not be ap plicable outside the exact regimen in which they were derived. A further co mplication is the chiral nature of these 2 drugs, with some suggestion that one enantiomer may have a favourable profile of metabolism over the other. That the oxazaphosphorines continue to be the subject of intensive investig ation over 30 years after their introduction into clinical practice is part ly because of their antitumour activity. Further advances in analytical and molecular pharmacological techniques may further optimise their use and al low rational design of more selective analogues.