Metabolism and Pharmacokinetics of Oxazaphosphorines

Abstract

The 2 most commonly used oxazaphosphorines are cyclophosphamide and ifosfamide, although other bifunctional mustard analogues continue to be investigated. The pharmacology of these agents is determined by their metabolism, since the parent drug is relatively inactive. For cyclophosphamide, elimination of the parent compound is by activation to the 4-hydroxy metabolite, although other minor pathways of inactivation also play a role. Ifosfamide is inactivated to a greater degree by dechloroethylation reactions. More robust assay methods for the 4-hydroxy metabolites may reveal more about the clinical pharmacology of these drugs, but at present the best pharmacodynamic data indicate an inverse relationship between plasma concentration of parent drug and either toxicity or antitumour effect. The metabolism of cyclophosphamide is of particular relevance in the application of high dose chemotherapy. The activation pathway of metabolism is saturable, such that at higher doses (greater than 2 to 4 g/m2) a greater proportion of the drug is eliminated as inactive metabolites. However, both cyclophosphamide and ifosfamide also act to induce their own metabolism. Since 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 between the cytochrome P450 isoforms responsible for the activating 4-hydroxylation reaction and those which mediate the dechloroethylation reactions, selective 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 saturation and autoinduction to the net activation of cyclophosphamide have been developed. However, these require careful validation and may not be applicable outside the exact regimen in which they were derived. A further complication 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 investigation over 30 years after their introduction into clinical practice is partly because of their antitumour activity. Further advances in analytical and molecular pharmacological techniques may further optimise their use and allow rational design of more selective analogues.

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

“…Cytochrome P450 2B6 is the most important isoform in this respect, and the liver is the main organ of this ratelimiting reaction resulting in 4-hydroxy-CPA (4-OH-CPA; ref. 18). Although activation might occur in tumor tissues, this unlikely accounts for a significant fraction of CPArelated cytotoxicity (19).…”

“…Interestingly, CPA in high doses is capable of inducing its own activation, which is mediated at least partially by cytochrome P 450 isoform 3A4 (CYP3A4) induction (21). CYP3A4 is also involved in a competing side chain oxidation of CPA, which results in N-dechloroethylation and the formation of the neurotoxic metabolite chloroacetaldehyde (18). However, the major detoxification pathway is the class 1 aldehyde dehydrogenase (ALDH)-mediated oxidation of aldophosphamide, the tautomer of 4-OH-CPA (18,22).…”

“…CYP3A4 is also involved in a competing side chain oxidation of CPA, which results in N-dechloroethylation and the formation of the neurotoxic metabolite chloroacetaldehyde (18). However, the major detoxification pathway is the class 1 aldehyde dehydrogenase (ALDH)-mediated oxidation of aldophosphamide, the tautomer of 4-OH-CPA (18,22). Consequently, increased intratumoral ALDH activity has been reported as a mechanism of resistance to CPA (23).…”

A virus-directed enzyme prodrug therapy (VDEPT) strategy for lung cancer using a CYP2B6/NADPH-cytochrome P450 reductase fusion protein

“…It is used for the treatment of breast cancer, as a critical component of the CMF regimen, in the treatment of patients with non-Hodgkin's lymphoma, a variety of bone and soft tissue sarcomas, and acute lymphoblastic leukemia. 8 CPA is a therapeutically inactive prodrug that requires bioactivation by CYP to exert its antitumor function. The primary 4 0 hydroxy metabolite is formed in the liver in a reaction mainly catalyzed by human CYP2B6, 5,9,10 and is in equilibrium with its ring opened tautomer, aldophosphamide.…”

“…11,12 In conventional chemotherapy, the active metabolites have to travel to the often distal tumor site to exert their cytotoxic effect. Therefore, high doses of CPA are used (up to 7 g/m 2 ) 8 to ensure that the levels of cytotoxic metabolites are sufficient at the tumor sites. These doses of CPA may result in toxicity (neurotoxicity, cardiotoxicity and bone marrow suppression).…”